Category Archives: Model System

Parkinson’s Awareness Month: The Science Behind How Exercise Slows Disease Progression

“Do not let what you cannot do interfere with what you can do.” John Wooden

“To enjoy the glow of good health, you must exercise.” Gene Tunney

Précis: For Parkinson’s Awareness Month, let’s begin with an important reminder/statement that “Exercise is medicine for Parkinson’s disease.”  Coming soon in a future blog post I will review the benefits of vigorous exercise in human Parkinson’s.  In today’s blog post, using an established mouse model of Parkinson’s disease and exercise, the recent paper from Wenbo Zhou and collaborators in Aurora, CO will be described. 

The full citation to this open-access paper is as follows: Wenbo Zhou, Jessica Cummiskey Barkow, Curt R. Freed. Running wheel exercise reduces α-synuclein aggregation and improves motor and cognitive function in a transgenic mouse model of Parkinson’s disease. PLOS ONE, 2017; 12 (12): e0190160 DOI: 10.1371/journal.pone.0190160

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“Health is the thing that makes you feel that now is the best time of the year.”Franklin P. Adams

The Neuroprotective Role of Exercise in Parkinson’s, A Quick Look Back: In my own academic career (during the past 30-something years) studying deep-vein thrombosis (hematology) and breast cancer cell migration/invasion (oncology) we used many different types of experimental techniques, specifically: developing protocols to purify blood proteins; three-dimensional molecular modeling; site-directed mutagenesis and expression of recombinant proteins; blood plasma-based model systems; cell-based model systems of cancer cell migration, invasion, and cell signaling; immunohistochemical (pathology) evaluation of human tissues; mouse model systems of cancer cell invasion and metastasis; and mouse model systems of venous thrombosis, aging, and wound healing/repair. I was very fortunate to be able to recruit some truly amazing graduate students and postdoctoral fellows to perform all of these studies.

Likewise, there are a lot of ways to study a disorder like Parkinson’s disease including model cell systems, model rodent systems, and human clinical trials. However, Parkinson’s is not an ‘easy’ human disease to characterize; even with the four Cardinal motor symptoms, we express our disorder slightly differently from one other.  In the past 20-25 years, from reading the literature, much has been learned and advanced with various rodent model systems of Parkinson’s. Studies began in the early 2000’s evaluating the role of exercise in rodent Parkinson’s model systems.  Four such papers (out of many) are highlighted below; with evidence for neuroprotection, neuro-restoration and neuroplasticity. In a 2001 study, Tillerson et al. concluded “These results  suggest that physical therapy may be beneficial in Parkinson’s disease.” Importantly, recent human clinical trials/studies are clearly showing positive results with exercise in Parkinson’s (depending on the study they have shown neuroprotection, improved motor defect and cognitive function gains).

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“Take care of your body. It’s the only place you have to live.” Jim Rohn

Highlights and Overview of “Running wheel exercise reduces α-synuclein aggregation and improves motor and cognitive function in a transgenic mouse model of Parkinson’s disease”:

  • Gene mutations that have been found to cause Parkinson’s include α-synuclein, Parkin, UCHL1, DJ-1, PINK1, LRRK2, and VSP35. These mutations result in loss of neuroprotection (e.g., DJ-1 and PINK1), or gain of toxic function (e.g., α-synuclein and LRRK2).
  • The protein α-synuclein is a major component of Lewy bodies that are the signature brain lesions in Parkinson’s. A mouse model that overexpresses human α-synuclein is very similar to the human condition.  The most neurotoxic form of α-synuclein are the α-synuclein oligomers, which implies that preventing α-synuclein aggregation could slow disease progression.
  • The focus of this research was the neuroprotective effects of exercise (running wheel) in mice and quantifying the effect from exercise; they found typically the mice ran >5miles/day.

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  • They found that one week of running wheel activity led to significantly increased DJ-1 protein concentrations in muscle and plasma in normal mice (compared to mice not running).  Furthermore, using a mouse model with DJ-1 genetically deleted, running wheel performance was much reduced indicating that DJ-1 is important for normal motor activity.
  • They then studied exercise in a mouse model expressing a mutant human form of α-synuclein that is found in all neurons- they wanted to see if exercise could prevent abnormal α-synuclein protein deposition and behavioral decline.
  • Their results showed that motor and cognitive performance were significantly better in exercising animals compared to control mice not allowed to run.
  • They found that the exercising mice had significantly increased levels of DJ-1, Hsp70 and BDNF concentrations and had significantly less α-synuclein aggregation in brain compared to control mice not allowed to run.
  • Interestingly, they also found that blood plasma concentrations of α-synuclein were significantly higher in exercising mice compared to control mice not allowed to run.
  • They conclude that exercise may be neuroprotective. Their results imply that exercise may slow the progression of Parkinson’s disease by preventing α-synuclein aggregation in brain.
  • Below are presentation of interesting results from Figures 4, 5, and 6:

Figure 4 (above) shows that exercise in the aged over-expressing α-synuclein mice had increased levels of DJ-1 (panel B), HSP70 (panel C) and BDNF (panel D) in their brains, and also increased DJ-1 levels in both muscle (panel F) and blood plasma (panel G), compared to non-exercise control mice.

Figure 5 (above) shows that exercise in the aged over-expressing α-synuclein mice had reduced formation of oligomeric α-synuclein (panel C is specific for human α-synuclein protein and panel D is for both mouse and human α-synuclein protein) compared to non-exercise control mice.

Figure 6 (above) shows that exercise in the aged over-expressing α-synuclein mice had increased α-synuclein concentration in blood plasma (panel C is specific for human α-synuclein protein and panel D is for both mouse and human α-synuclein protein) compared to non-exercise control mice.

“I have two doctors, my left leg and my right.” G.M. Trevelyan

Exercise Slows Progression of Parkinson’s: This was both a straightforward and elegant study that gives mechanistic insight into the positive benefits of exercise in Parkinson’s. Here is how it could hopefully be translated from mouse to man: (1) Exercise prevents α-synuclein oligomer accumulation in brain; reduced in brain and increased (monomers and dimers) in blood plasma.  (2) Exercise significantly improved motor and cognitive function.  (3) The benficial effects of exercise is partly related to increased levels of DJ-1, Hsp70 and BDNF, which are neuroprotective substances. (4)  It is not possible to totally define/describe how exercise alters brain function in Parkinson’s when exercise itself produces such widespread systemic changes and benefits.

In conclusion, this study clearly demonstrates the neuroprotective effect of exercise.  It almost seems that exercise made the brain behave like a molecular-sieve to filter out the toxic oligomeric α-synuclein protein and it accumulated in the bloodstream.  Exercise works by slowing the progression of Parkinson’s. 

“If you always put limit on everything you do, physical or anything else. It will spread into your work and into your life. There are no limits. There are only plateaus, and you must not stay there, you must go beyond them.” Bruce Lee

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Neuroprotection with Taurine in a Parkinson’s Model System

“There is no medicine like hope, no incentive so great, and no tonic so powerful as expectation of something tomorrow.” Orison Swett Marden

“Hope sees the invisible, feels the intangible, and achieves the impossible.” Helen Keller

Introduction: Many of us take levodopa/carbidopa for substantial symptomatic relief; however, this dopamine replacement treatment only relieves symptoms without offering either neuroprotection or neuro-restoration. We are still anxiously waiting for the study to be released that announces “We describe a new Parkinson’s compound and we’ve nicknamed it hopeful, helpful, and protective“.   Today’s post will review an interesting paper from Yuning Che and associates in Dalian, China recently published in Cell Death and Disease (open access, click here to download paper).  The ‘hopeful’ neuroprotective compound is the amino sulfonic compound taurine.  Before we get lost in all of the possibilities, let’s discuss the science and see what they describe, ok? First, we begin with some background.

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“I truly believe in positive synergy, that your positive mindset gives you a more hopeful outlook, and belief that you can do something great means you will do something great.” Russell Wilson

Neuroinflammation and Oxidative Stress are Pathological Processes that  Promote the Development of Parkinson’s:   Parkinson’s is a neurodegenerative disorder where we lose dopamine-producing neurons in the mid-brain substantia nigra.   There are several pathological patterns known to contribute to the development of Parkinson’s as highlighted below.  Related to this post is the negative-effect contributed by long-term neuroinflammation and oxidative stress.

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“It’s hope as a decision that makes change possible.” Jim Willis

Macrophages in the Brain are Called Microglia Cells:  In many instances, the body initiates and uses the pro-inflammatory machinery as a host-defense response; in other words, we use it to protect ourselves.  When it gets highjacked and becomes detrimental to be host, we realize the sheer firepower of our inflammatory system.  The good-and-the-bad of inflammation is mediated primarily by the cells named neutrophils (along with the eosinophils and basophils), monocytes and macrophages.  The monocyte leaves the bloodstream and migrates to various organs/tissues where it can ‘mature’ into a macrophage, which is a ‘field commander’ type-of-cell.  Think of a macrophage as a General in the bunker of a battlefield, not only giving detailed marching orders but they are also leading the charging brigade of soldiers.  Macrophages in the brain are named microglia cells .  First, macrophages (microglia cells) are ‘phagocytic’ cells that are capable of engulfing foreign-damaged-invading substances/cells (phagocyte comes from the Greek phagein, “to eat” or “devour”, and “-cyte”, the suffix in biology denoting “cell”).  Second, macrophages (microglia cells) direct the inflammatory response by releasing all kinds of substances that give other inflammatory/immune cells their instructions.  Sometimes these cells and their instructions become bad to the neighboring tissue/organs; in our case, the dopamine-produing neurons in the midbrain.

activated_microgliaMicroglia-mediated neuroinflammation(Figure credit): Various substances initiate contact with resting unstimulated microglia cells.  This ‘activates’ the microglia cell into an cell of considerable fire-power by producing and releasing many substances [nitric oxide (NO), reactive oxygen species (ROS),  and several inflammatory cytokines (e.g., IL-1, IL-6, and  TNF-alpha)]. This collection of pro-inflammatory substances secreted by the activated microglia cells creates a hostile microenvironment that promotes neuronal cell dysfunction and potential death to the cell.

Depending on the need and response of the ‘environmental challenge’, macrophages (microglia cells) can be activated to become either ‘M1’ (focused on becoming a pro-inflammatory) microglia cell or ‘M2’ (transforms into an anti-inflammatory) microglia cell [see Figure below, credit].  In the setting of an invasion or infiltration by microbes, you would want the microglia cell to be activated to a M1 state’ they could attack, engulf and kill the invading microorganism. In this setting, the M1 microglia cell would be protective of you. By contrast, the role of M2 microglia cells would be to turn-off the resultant pro-inflammatory response.  This implies that long-term inflammatory events that promote inappropriate M1 microglia cell activation could lead to dysfunction and even cell/tissue death. This description of appropriate/inapproriate microglia cell activation illustrates the complex nature of these inflammatory cells. What this says is in Parkinson’s, chronic activation to M1 microglia cells could generate a detrimental neuroinflammatory environment able to attack host cells/tissues.

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“It is difficult to say what is impossible, for the dream of yesterday is the hope of today and the reality of tomorrow.” Robert H. Goddard

Taurine: Taurine is an amino sulfonic compound (many erronously use the term amino acid) and it is considered to be a conditionally essential nutritient.  We do not use taurine in the assembly of proteins from genes; however, it participates in several physiological systems.  Taurine is apparently a popular additive/supplement in many different energy drinks.  Both WebMD (click here) and the Mayo Clinic (click here) have posted overviews of taurine and consider it mostly safe.  The structure of taurine is shown below (credit). Taurine is found in the brain, heart, muscle and in many other organs.  Good sources of dietary taurine are animal and fish proteins. An interesting overview for using taurine to stay healthy and to promote longevity has recently been posted (click here). Taurine has many proposed physiological functions that range from neurotransmitter to cell anti-oxidant, from anti-inflammatory to enhancing sports performance.  The ‘problem’ with having a multi-talented substance like taurine is actually studying these diverse functions individually and trying to test them in rigorous scientific studies, which leads us (finally!) to the paper introduced at the beginning.

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“Hope is the mainspring of life.” Henry L. Stimson

Taurine protects dopaminergic neurons in a mouse Parkinson’s disease model through inhibition of microglial M1 polarization: Here are some key aspects to this  study:

  • It is becoming more evident that neuroinflammation and oxidative stress are likely key participants to the development of Parkinson’s.
  • Surrounding the substantia nigra are a lot of unactivated microglia cells, which when activated to become M1 microglia cells they secrete several cytotoxic compounds that can easily harm or kill dopaminergic-producing neurons.
  • In particular, these neurons are susceptible to ‘injury’ due to their low antioxidant potential, low levels of calcium, increased amounts of iron, and the oxidation-susceptible dopamine.
  • Taurine has been shown in several reports to be a neuromodulating substance, boosting intracellular levels of calcium, anti-oxidant, and anti-inflammatory.
  • A recent report linked motor severity in Parkinson’s to low levels of taurine in blood plasma.
  • The authors tested a hypothesis that the supplementation with exogenous taurine might be neuroprotective in a Parkinson’s model sy\stem.
  • Previous studies have revealed a neuroprotective role for taurine in both glutamate-induced and hypoxic-ischemic brain models.
  • They used a mouse model of Parkinson’s caused by injection with paraquat and maneb [(P + M) a two-pesticide model of Parkinson’s], which showed progressive dopaminergic neurodegenera-
  • tion, gait abnormality and α-synuclein aggregation.
  • Taurine treatment protected the mouse from the detrimental effect of  P + Mu.
  • Their results revealed three effects of taurine in the P + M model of Parkinson’s (i) inhibition of microglia cell activation; (ii) reduced M1 microglia cell polarization; and (iii) reduced activation of cellular NOX2 and nuclear factor-kappa B (NF-κB).

“Losing the possibility of something is the exact same thing as losing hope and without hope nothing can survive.” Mark Z. Danielewski

Overview of Some of Their Results: Figure 1 presents the effect of P + M to promote a pathological state that resembles Parkinson’s.  Panels 1A and 1B show the loss of dopaminergic neurons by the staining of the brain with an antibody to tyrosine hydroxylase (a major dopaminergic neuron protein) following P + M injection.  Panels !C and 1D show that P + M treatment lead to expression of the toxic olgiometic α-synuclein.  Not shown here, but P + M treatment resulted in displayed abnormal gaits (Figure 2 in the paper). Screenshot 2018-04-05 11.18.39

Taurine protected against P + M-mediated neurotoxicity.  Using the same tests as done in Figure 1 above, taurine preserved neurons even with P + M present (Figure 3 panels A and B) and taurine reduced expression of oligomeric α-synuclein in the presence of P + M (Figure 3 panels C and D).  Not included here, the protective effects of taurine during P + M treatment was partly due to the inhibition of migroglia cell-mediated chronic inflammation.  Furthermore, the ability of microglia cells to become  ‘polarized’ or activated to either M1 (pro-inflammatory) or M2 (anti-inflammatory) was also studied in the presence of taurine plus P + M-treatment.  Both M1 and M2 microglia cells are present in the mid-brain of the mice treated with P + M; interestingly, taurine treatment reduced expression levels of damaging M1 microglia cell products (results not included here).  Finally, two key M1-linked gene products were studied, NOX2 and NF-kB.  They found that taurine was able to reduce expression of both NOX2 and NF-kB, which indicates that taurine blocked these key products important for neuroinflammation (NOX2) and polarization of the M1 microglia cell-type (NF-kB)

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“The present is the ever moving shadow that divides yesterday from tomorrow. In that lies hope.” Frank Lloyd Wright

What do these results show? (1) In an interesting model of Parkinson’s, taurine showed  a potent benefit to the mice; (2) taurine reduced loss of dopamine-producing neurons in P + M mice; (3) taurine reduced oligomeric α-synuclein in P + M mice; (4) taurine treatment reduced neuroinflammation by suppressing M1 microglia cells to suggest a neuroprotectice effect; and finally, (5) taurine reduced expression of both NOX2 and NF-kB,  important genes for microglia cell activation. A similar neuroprotective effect was also found for taurine in an experimental model of Alzheimer’s disease, which resulted in improved coognitive ability. The Parkinson’s model clearly suggests that disease progression by P + M treatment is promoted by chronic neuroinflammation and M1-type microglia cells.  Under the test conditions used, taurine was shown to convincingly reduce dopamine-producing neuronal cell degeneration in the presence of the pesticides P + M.

What do these results suggest? There is still much to learn about taurine. There is much potential to taurine being neuroprotective.  However, there have been other seriously–convincing-positive mouse model results with other compounds that failed miserably in human clinical trials.  The data shown here uses an interesting mouse model of Parkinson’s with a simple yet elegant and solid set of data (that does not appear to be overly interpreted).  Taurine has been shown to be safe in treating other human maladies (diabetes and cardiovascular disease).  The results here are hopeful that taurine could provide neuroprotection in human Parkinson’s. Hopefully, clinical trials will be started somewhere soon to determine the ability of taurine to provide neuroprotection in human Parkinson’s disease.

“Every one of us is called upon, perhaps many times, to start a new life. A frightening diagnosis, a marriage, a move, loss of a job…And onward full-tilt we go, pitched and wrecked and absurdly resolute, driven in spite of everything to make good on a new shore. To be hopeful, to embrace one possibility after another–that is surely the basic instinct…Crying out: High tide! Time to move out into the glorious debris. Time to take this life for what it is.” Barbara Kingsolver

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The Yack on NAC (N-Acetyl-Cysteine) and Parkinson’s

“Once you choose hope, anything’s possible.” Christopher Reeve

“Hope is like a road in the country; there was never a road, but when many people walk on it, the road comes into existence.” Lin Yutang

Introduction: N-Acetyl-Cysteine (or N-acetylcysteine, usually abbreviated NAC and frequently pronounced like the word ‘knack’) is an altered (modified by an N-acetyl-group) form of the sulfur-containing amino acid cysteine (Cys).  NAC is one of the building blocks for the all important antioxidant substance glutathione (GSH).   GSH is a powerful reagent that helps cells fight oxidative stress.  One of the putative causes of Parkinson’s is oxidative stress on dopamine-producing neurons (see figure below). This post summarizes some of the biochemistry of NAC and GSH.  Furthermore, NAC may provide some neuroprotective benefit as a complementary and alternative medicine (CAM) approach to treating Parkinson’s.

“Losing the possibility of something is the exact same thing as losing hope and without hope nothing can survive.” Mark Z. Danielewski

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 Glutathione (GSH):  GSH is a 3-amino acid substance (tripeptide) composed of Cys linked to glutamate (Glu) and followed by glycine (Gly). NAC would need to be de-acetylated to provide Cys and that would feed in to the reaction synthesis. Importantly, Cys is the rate limiting reactant, which means without adequate amounts of Cys you do not make GSH.   The schematic below gives the orientation and order of addition of the three amino acid components to give you GSH.

NACtoGSH

There are two advantages of NAC over Cys for making GSH: (i) the sulfhydryl group of NAC remains reduced (that is as an SH group) more so than the SH group of Cys; and (ii) the NAC molecule appears to transport itself through cell membranes much more easily than Cys.  The reduced (i.e.,  free SH group) form of GSH, once synthesized within the cell, has several key functions that range from antioxidant protection to protein thiolation to drug detoxification in many different tissues.   The key function of GSH is to provide what is known as “reducing equivalents” to the cell, which implies an overall key antioxidant effect.

The schematic below shows NAC transport from extracellular to intracellular (inside the cell), and the primary reactions for detoxification and thiolation from GSH. Implied by this figure below is that GSH is not easily transported into the cell. Furthermore, in a more toxic/hostile environment outside of the cell, you can easily oxidize 2 GSH molecules to become GSSG (the reduced SH group gets oxidized to form an S-S disulfide bond) and GSSG does not have the antioxidant effect of GSH.   However, inside the cell, GSH is a very potent antioxidant/detoxifying substance. And the beauty of being inside the cell, there is an enzyme called GSH-reductase that regenerates GSH from GSSG.

Rushworth-NAC.review-4.2

To recap and attempt to simplify what I just said, NAC gets delivered into a cell, which then allows the cell to generate intracellular GSH.  The presence of intracellular GSH gives a cell an enormous advantage to resist potentially toxic oxidative agents. By contrast, extracellular GSH has a difficult path into the cell; and is likely to be oxidized to GSSG and rendered useless to help the cell.

“Just remember, you can do anything you set your mind to, but it takes action, perseverance, and facing your fears.”  Gillian Anderson

One of many biological functions of NAC:   Perhaps the most important medical use of NAC is to help save lives in people with acetaminophen toxicity, in which the liver is failing.  How does NAC do this?  Acetaminophen is sold as Tylenol.  It is also added to compounds that are very important for pain management ()analgesics), including Vicodin and Percocet. Acetaminophen overdose is the leading cause of acute liver failure in the USA.   This excess of acetaminophen rapidly consumes the GSH in the liver, which then promotes liver death.  NAC quickly restores protective levels of GSH  to the liver, which hopefully reverses catastrophic liver failure to prevent death.

Systemically, when taken either orally or by IV injection, NAC would have 2 functions.  First, NAC replenishes levels of Cys to generate the intracellular antioxidant GSH (see schemes above).  Second, NAC has been shown to regulate gene expression of several pathways that link oxidative stress to inflammation.  Since the primary goal of this post relates to NAC as a CAM in Parkinson’s, I will not expand further on the many uses of NAC in other disease processes.  However, listed at the end are several review articles detailing the numerous medicinal roles of NAC.

“Love, we say, is life; but love without hope and faith is agonizing death.” Elbert Hubbard

Use of NAC as a CAM in Parkinson’s:   This is what we know about oxidative stress in Parkinson’s and the potential reasons why NAC could be used as a CAM in this disorder, it goes as follows  (it’s also conveniently shown in the figure at the bottom):

1. Substantia nigra dopamine-producing neurons die from oxidative stress, which can lead to Parkinson’s.

2.What is oxidative stress? Oxidative stress happens when your cells in your body do not make/have enough antioxidants to reduce pro-oxidants like free radicals. Free radicals cause cell damage/death when they attack proteins/cell membranes.

3.We speak of oxidative stress in terms of redox imbalance (which means the balance between increased amounts of oxidants or  decreased amounts of antioxidants).

4.Glutathione (GSH) is a key substance used by cells to repair/resist oxidatively damaged cells/proteins.

5.”Forces of evil” in the brain that make it difficult to resist oxidative stress:  decreased levels of GSH,  increased levels of iron and  increased polyunsaturated fatty acids.

6.Extracellar GSH cannot be transported easily into neurons, although there is evidence GSH gets past the blood brain barrier;

7.N-acetyl Cysteine (NAC), is an anti-oxidant and a precursor to GSH.  NAC gets through the blood brain barrier and can also be transported into neurons.

8.Cysteine is the rate-limiting step for GSH synthesis (NAC would provide the cysteine and favor synthesis of GSH).

9.Animal model studies have shown NAC to be neuroprotective.

10. Recent studies have shown NAC crosses the human blood brain barrier and may be a useful PD-modifying therapy.

 

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“You cannot tailor-make the situations in life but you can tailor-make the attitudes to fit those situations.”  Zig Ziglar

Scientific and clinical support for NAC in treating Parkinson’s: Content presented here is meant for informational purposes only and not as medical advice.  Please remember that I am a basic scientist, not a neurologist, and any use of these compounds should be thoroughly discussed with your own personal physician. This is not meant to be an endorsement  because it would be more valuable and important for your neurologist to be in agreement with the interpretation of these papers.

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To evaluate the use of NAC in Parkinson’s, Katz et al. treated 12 patients with Parkinson’s with oral doses of NAC twice a day for two days.   They studied three different doses of 7, 35, and 70 mg per kilogram. For example, in a person weighing 170 pounds, from a Weight Based Divided Dose Calculator (click here), this would be 540, 2700, and 5400 mg/day of NAC for 7, 35, and 70 mg/kg, respectively. Using cerebral spinal fluid (CSF), they measured levels of  NAC, Cys, and GSH at baseline and 90 minutes after the last dose. Their results showed that there was a dose-dependent range of NAC as detected by CSF. And they concluded that oral administration of NAC produce biologically relevant CSF levels of NAC at the three doses examined; the doses of oral NAC were also well-tolerated.  Furthermore, the patients treated with NAC had no change in either motor or cognitive function. Their conclusions support the feasibility of using oral NAC as a CAM therapy for treatment of Parkinson’s.

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In a separate study, Monti at al  presented some preliminary evidence for the use of NAC in Parkinson’s. The first part of their study consisted of a neuronal cell system that was pre-treated with NAC in the presence of the pesticide rotenone as a model of Parkinson’s.   These results showed that with NAC there was more neuronal cell survival after exposure to rotenone compared to the rotenone-treated cells without NAC. The second part of the study was a small scale clinical evaluation using NAC in Parkinson’s. These patients were randomized and given either NAC or nothing and continued to use their traditional medical care. The patients were evaluated at the start and after three months of receiving NAC; they measured dopamine transporter binding and  performed the unified Parkinson’s disease rating scale  (UPDRS) to measure clinical symptoms. The clinical study revealed an increase in dopamine transporter binding in the NAC treatment group and no measurable changes in the control group. Furthermore UPDRS scores were significantly improved in the NAC treatment group compared to the control patient group.   An interesting feature of this study was the use of pharmaceutical NAC, which is an intravenous (IV) medication and they also used 600 mg NAC tablets. The dose used was 50 mg per kg mixed into sterile buffer and infused over one hour one time per week. In the days they were not getting the IV NAC treatment, subjects took 600 mg NAC tablets twice per day.

 Okay, what did I just say? I will try to summarize both of these studies in a more straightforward manner.   The results above suggest that NAC crosses the blood brain barrier and does offer some anti-oxidative protection. In one study, this was shown by increased levels of both GSH and Cys dependent on the NAC dose. In another study, they directly measured dopamine transporter binding, which was increased in the presence of NAC. In the second study using a three month treatment strategy with NAC, there was a measurable positive effect on disease progression as measured by UPDRS scores.  

“Our greatest weakness lies in giving up. The most certain way to succeed is always to try just one more time.” Thomas A. Edison

Potential for NAC in treating Parkinson’s: Overall, both studies described above suggest the possibility that NAC may be useful in treating Parkinson’s. However, in both cases these were preliminary studies that would require much larger randomized double-blind placebo-controlled trials to definitively show a benefit for using NAC in treating Parkinson’s. On a personal note, I have been taking 600 mg capsules of NAC three times a day for the past year with the hope that it is performing the task as outlined in this post. Using information from the first study that would be a NAC dose of 24 mg per kilogram body weight. In conclusion, the information described above suggests that NAC may be useful in regulating oxidative stress, one of the putative causes of Parkinson’s. As with all studies, time will tell if ultimately there is a benefit for using NAC in Parkinson’s.

“I am not an optimist, because I am not sure that everything ends well. Nor am I a pessimist, because I am not sure that everything ends badly. I just carry hope in my heart. Hope is the feeling that life and work have a meaning. You either have it or you don’t, regardless of the state of the world that surrounds you. Life without hope is an empty, boring, and useless life. I cannot imagine that I could strive for something if I did not carry hope in me. I am thankful to God for this gift. It is as big as life itself.” Vaclav Havel

References Used:
Katz M, Won SJ, Park Y, Orr A, Jones DP, Swanson RA, Glass GA. Cerebrospinal fluid concentrations of N-acetylcysteine after oral administration in Parkinson’s disease. Parkinsonism Relat Disord. 2015;21(5):500-3. doi: 10.1016/j.parkreldis.2015.02.020. PubMed PMID: 25765302.

Martinez-Banaclocha MA. N-acetyl-cysteine in the treatment of Parkinson’s disease. What are we waiting for? Med Hypotheses. 2012;79(1):8-12. doi: 10.1016/j.mehy.2012.03.021. PubMed PMID: 22546753.

Monti DA, Zabrecky G, Kremens D, Liang TW, Wintering NA, Cai J, Wei X, Bazzan AJ, Zhong L, Bowen B, Intenzo CM, Iacovitti L, Newberg AB. N-Acetyl Cysteine May Support Dopamine Neurons in Parkinson’s Disease: Preliminary Clinical and Cell Line Data. PLoS One. 2016;11(6):e0157602. doi: 10.1371/journal.pone.0157602. PubMed PMID: 27309537; PMCID: PMC4911055.

Mosley RL, Benner EJ, Kadiu I, Thomas M, Boska MD, Hasan K, Laurie C, Gendelman HE. Neuroinflammation, Oxidative Stress and the Pathogenesis of Parkinson’s Disease. Clin Neurosci Res. 2006;6(5):261-81. doi: 10.1016/j.cnr.2006.09.006. PubMed PMID: 18060039; PMCID: PMC1831679.

Nolan YM, Sullivan AM, Toulouse A. Parkinson’s disease in the nuclear age of neuroinflammation. Trends Mol Med. 2013;19(3):187-96. doi: 10.1016/j.molmed.2012.12.003. PubMed PMID: 23318001.

Rushworth GF, Megson IL. Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits. Pharmacol Ther. 2014;141(2):150-9. doi: 10.1016/j.pharmthera.2013.09.006. PubMed PMID: 24080471.

Taylor JM, Main BS, Crack PJ. Neuroinflammation and oxidative stress: co-conspirators in the pathology of Parkinson’s disease. Neurochem Int. 2013;62(5):803-19. doi: 10.1016/j.neuint.2012.12.016. PubMed PMID: 23291248.

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2016: The Year in Parkinson’s

“The most beautiful experience we can have is the mysterious. It is the fundamental emotion that stands at the cradle of true art and true science.” Albert Einstein

“Your assumptions are your windows on the world. Scrub them off every once in a while, or the light won’t come in.” Isaac Asimov

Summary: (Part 1) A brief review of my year with Parkinson’s. (Part 2) An overview of 12 scientific research studies on Parkinson’s from 2016.

Part 1. A personal Parkinson’s 2016 calendar review

Life with Parkinson’s: 706 days ago I started this blog ‘Journey with Parkinson’s’; and it’s been a remarkable journey through time since then.  Life is full, rarely a dull moment.  Dealing with a disorder like Parkinson’s is difficult because it slowly creeps around your body, somewhat stealth by nature but always ever present.  It requires a daily inventory of body movements, mental capacity and overall self-feelings compared to the day-week-month-year before.

Life is loving, fun, intellectually challenging, active, full, rarely a moment off; however, its best that way for me.  I close this paragraph by repeating two quotes from last year. They remind me to simply try to live as best as I am able for as long as I can.  My hope for you is likewise as well; keep going, keep working, stay active, stay the course.  Please make a manageable life-plan/contract with your care-partner, family and close friends; keep going, and please don’t give up.

“Never confuse a single defeat with a final defeat.” F. Scott Fitzgerald

“If you fell down yesterday, stand up today.” H.G. Wells

My year with Parkinson’s: To highlight my 2016, I’ve chosen 1 event/month to describe (not mentioned are the trips to the beach/vacation with Barbara, golf with the golf buddies, and other activities related to education, research and outreach for Parkinson’s.)  I am a very fortunate person.

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January-June, 2016:
(JAN) The 22nd year/class of undergraduates taking my spring semester course on ‘Biology of Blood Diseases’, great fun!
(FEB) An anniversary dinner with Barbara, a most loving person and the best care-partner.
(MAR) Started work on the WPC Parkinson Daily (eNewspaper) for the World Parkinson Congress).
(APR) Compiled all of the quotes from the students in class that led to the Kindle version (2016)/Paperback version (2017) of “A Parkinson’s Reading Companion”  (Click here to read about it).
(May) Graduation ceremonies are always on Mother’s Day weekend; it is filled with joy and regalia, promise and the future ahead for all of the graduates (typically, I attend the medical school ceremony on Saturday and as many undergraduate ceremonies on SAT-SUN my schedule permits (picture above is from the Dept. Biology commencement).
(JUN) A weekend in the Smoky Mountains in Asheville, NC: to attend a Parkinson’s retreat, to relax-renew-play golf, and to get a second Parkinson’s-related tattoo.

“Be happy for this moment. This moment is your life.” Omar Khayyam

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July-December, 2016:
(JUL) A weekend in Greenville, SC to participate and get certified in PWR! (Parkinson Wellness Recovery); an amazing experience (click here to read blog post about it).
(AUG) Truly a professional highlight of my career being chosen by the medical students to deliver the 2016 Richard H. Whitehead Lecture (click here to read blog post about it).
(SEP) Attended and presented a poster at the 4th World Parkinson Congress (WPC) in Portland, OR (click here to read about the WPC).
(OCT) Moving Day® NC Triangle, National Parkinson Foundation; great team and such a fun day/experience (click here to read about NC Triangle Moving Day).
(NOV) Research proposal submitted on the role of proteases and their inhibitors, alpha-synuclein and exercise in Parkinson’s. It is something I’ve been thinking about all of last year (click here to read about the funding program).
(DEC) Finished teaching the 3rd class of the Honor’s-version and fall semester of the undergraduate ‘Biology of Blood Diseases’ course; a great honor for me.

“Success is not the key to happiness. Happiness is the key to success. If you love what you are doing, you will be successful.” Albert Schweitzer

Part 2. The year (2016) in Parkinson’s science

Parkinson’s with a hopeful future: To live successfully with a chronic and progressing neurodegenerative disorder like Parkinson’s requires much, but in the least it takes hope.  We must remain hopeful that advances in Parkinson’s treatment are being made and that our understanding of the science of Parkinson’s is continuing to evolve.

Parkinson’s research: Parkinson’s is the most prevalent neurodegenerative movement disorder.  According to PubMed, there were 6,782 publications in 2016 that used “Parkinson’s disease” in the Title/Abstract.  Likewise in 2016, PubMed had 9,869 and 1,711 citations on Alzheimer’s disease and on Amyotrophic Lateral Sclerosis (ALS), respectively. Most research studies move in incremental steps; we describe a hypothesis and collect the data to hopefully advance us forward.

2016, the year in Parkinson’s: To remind us of some of these forward steps in Parkinson’s research, and to add to our base-level of hope, here are 12 projects from 2016 regarding Parkinson’s (there are several studies, not mentioned here, that I’m currently working on for individual blog posts because they seemed super-relevant and in need of more thorough presentation/explanation).  Although 12 is a minuscule list of citations/work reported from last year, it reinforces a simple notion that our trajectory is both positive and hopeful.

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January, 2016: Dipraglurant FDA-approved to treat dyskinesia. After ~5 years of treatment with the ‘gold-standard’ Levodopa/Carbidopa, many people-with-Parkinson’s develop drug-induced involuntary movement (also called dyskinesia).  This can be a serious side-effect of levodopa, and it can lead to numerous detrimental consequences.  The pharmaceutical company, Addex Therapeutics, has received orphan drug status for their drug named Dipraglurant, which will be used for the treatment of levodopa-induced dyskinesia.  Click here to read about the putative molecular mechanism of Dipraglurant, what advantages Addex gains from the designated orphan-drug status, and for more information about Addex.

“January is here, with eyes that keenly glow, A frost-mailed warrior striding a shadowy steed of snow.” Edgar Fawcett

February, 2016: Early detection of Parkinson’s from mouth salivary gland biopsy.   There is no definitive test to identify Parkinson’s in its early stages.  Finding an easily accessible tissue for  biopsy  to help with the diagnosis would be of value.  From autopsy samples, the submandibular saliva glands in the mouth seemed to be a relevant and easily accessible site to study.  The test involved inserting a needle into the submandibular salivary gland under the jaw,  staining for modified-a-synuclein.   The results revealed  that Parkinson’s patients had  increased level of a-synuclein  compared to patients  without Parkinson’s.  Click here to view this paper: Adler, Charles H. et al. “Peripheral Synucleinopathy in Early Parkinson’s Disease: Submandibular Gland Needle Biopsy Findings.” Movement disorders : official journal of the Movement Disorder Society 31.2 (2016): 250–256. PMC. Web. 13 Feb. 2017.

“Even though February was the shortest month of the year, sometimes it seemed like the longest.” Lorraine Snelling

March, 2016:  Three-dimensional scaffold used  to grow neuronal cells for transplant to brain.  Scientists have been able to convert adult stem cells into neuronal cells by culturing the stem cells in three-dimensional  scaffolding.   There are many obstacles successfully using stem cells to treat Parkinson’s disease; one of them is converting the stem cells into dopamine-producing-neuronal cells to replace the dead brain cells of the patient.   The three-dimensional scaffolding facilitated which allowed the neuronal cells to be injected into mice. Hopefully, this approach will eventually be ready for testing in humans; however, this is a potential glimpse to the future. To read this research paper, click here: “Generation and transplantation of reprogrammed human neurons in the brain using 3D microtopographic scaffolds” by Aaron L. Carlson et al., in Nature Communications. Published online March 17 2016 doi:10.1038/ncomms10862

“It was one of those March days when the sun shines hot and the wind blows cold: when it is summer in the light, and winter in the shade.” Charles Dickens, Great Expectations

April, 2016: Role of Mer and Axl in immune clearance of neurons in Parkinson’s.
TAM receptors are found on immune system cells and they help clear out dead cells  generated by out bodies.  Two of the TAM receptors, dubbed Mer and Axl, help immune cells called macrophages act as garbage collectors. This study asked whether or not the brain microglial cells (brain macrophages) had such activity through Mer and Axl.  Interestingly, in mice lacking Mer and Axl, neurons regenerated much more rapidly in certain areas of the brain. Furthermore, microglial expression of Axl was upregulated in the inflammatory environment in a mouse model of Parkinson’s.  These results identify TAM receptors as controllers of microglial scavenger activity and also as potential therapeutic targets for Parkinson’s.  Click here to view this article: Fourgeaud, L., et al. (2016). “TAM receptors regulate multiple features of microglial physiology.” Nature 532(7598): 240-244.

“April hath put a spirit of youth in everything. (Sonnet XCVIII)”  William Shakespeare, Shakespeare’s Sonnets

May, 2016:  Complex genetics found in the study of Parkinson’s in human brain tissue.  Genetic changes were found in Parkinson’s disease and Parkinson’s disease dementia.  A team of scientists used RNA sequencing to illuminate two phenomena linked with the onset of Parkinson’s disease: specifically, differential gene expression and alternative splicing of genes. The study describes 20 differentially expressed genes in Parkinson’s and Parkinson’s dementia, comparing these with healthy controls. Genes showing over-expression included those involved with cell movement, receptor binding, cell signaling and ion homeostasis. Under-expressed genes had an involvement with hormone signaling.  These results increase our understanding of Parkinson’s; furthermore, the complexity of their results suggest we may be able to achieve a more detailed diagnosis .  Click here to view paper: Henderson-Smith, Adrienne et al. “Next-Generation Profiling to Identify the Molecular Etiology of Parkinson Dementia.” Neurology: Genetics 2.3 (2016): e75.

“May, more than any other month of the year, wants us to feel most alive.” Fennel Hudson

June, 2016: Mutations in a gene called TMEM230 causes Parkinson’s. The role of TMEM230  was found to be in packaging the neurotransmitter dopamine in neurons.  Interestingly, TMEM230 bridges membranes in synaptic vesicles; these vesicles are storage reservoirs for neurotransmitters. Since the loss of dopamine-producing neurons defines Parkinson’s, a defect in TMEM230 implies a new link to a genetic cause of Parkinson’s.  The research team identified this mutation in Parkinson’s patients in North America and Asia. Click here to view paper: Deng, H-X, et al., “Identification of TMEM230 mutations in familial Parkinson’s disease”. Nature Genetics 48, 733–739 (2016).

“I wonder what it would be like to live in a world where it was always June.”  L.M. Montgomery

July, 2016: Improving deep brain stimulation (DBS), one patient at a time.  Instead of one-size-fits-all, these researchers are pioneering a novel strategy for fine-tuning DBS on each person’s individual physiology.  Their DBS platform, termed Phasic Burst Stimulation, has the potential to (i) enhance therapeutic efficacy, (ii) extend battery lifespan; (iii) reduce detrimental side effects, and (iv)  adjust as each person’s motor symptoms change.  This tuning-based DBS approach has real promise.  Click here to view paper: “Phasic Burst Stimulation: A Closed-Loop Approach to Tuning Deep Brain Stimulation Parameters for Parkinson’s Disease.” by A.B. Holt et al., PLOS Computational Biology, http://dx.doi.org/10.1371/journal.pcbi.100501

“My life, I realize suddenly, is July. Childhood is June, and old age is August, but here it is, July, and my life, this year, is July inside of July.” Rick Bass

August, 2016: Comparison of different movement disorders to better understand Parkinson’s.  These researchers compared multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) to Parkinson’s.  MSA and PSP are progressive disorders that also cause changes in balance and walking.  The study consisted of  functional magnetic resonance imaging (fMRI) brain scans with each person using a grip strength exercise, which showed changes in the regions of brain that control muscle movement. Parkinson’s patients showed changes in the putamen and the primary motor cortex;  MSA patients had changes in the primary motor cortex, the supplementary motor area and the superior cerebellum. PSP patients showed a change in all four areas.  Normal healthy controls had no changes. These detailed results (i) show the progression of each movement disorder and (ii) indicate that biomarkers for these specific-regions of the brain might be useful for not only monitoring disease progression but also response to therapy. Click here to view article: Burciu et al., “Functional MRI of disease progression in Parkinson disease and atypical parkinsonian syndromes.”, Burciu, Chung, Shukla, Ofori, McFarland, Okun, Vaillancourt, Neurology, 016 Aug 16;87(7):709-17. doi: 10.1212/WNL.0000000000002985

“The month of August had turned into a griddle where the days just lay there and sizzled.” Sue Monk Kidd, The Secret Life of Bees

September, 2016: Preventing falls by combining virtual reality and treadmill training.   Falling down is one of the most common and most detrimental problems in the elderly  with Parkinson’s. This research team combined treadmill use with virtual reality training. They tested a large group of older adults at high risk for falls; they found that treadmill training with virtual reality led to reduced fall rates compared to treadmill training alone.Click here to view article: Mirelman et al.,  “Addition of a non-immersive virtual reality component to treadmill training to reduce fall risk in older adults (V-TIME): a randomised controlled trial”, The Lancet, 2016 Sep 17;388(10050):1170-82. doi: 10.1016/S0140-6736(16)31325-3

“By all these lovely tokens September days are here, With summer’s best of weather And autumn’s best of cheer.”  Helen Hunt Jackson

October, 2016: Caffeine-based compounds stop alpha (a)-synuclein misfolding in a yeast model of Parkinson’s. The aggregation (misfolding) of the protein a-synuclein is thought to be a key contributing factor in neuronal cell death that leads to Parkinson’s.  The misfolded a-synuclein ultimately forms what are termed Lewy bodies, which produce much neuronal cell morbidity and mortality. Caffeine has been shown to be  somewhat protective against Parkinson’s. The study here made double-headed constructs of compounds using caffeine and nicotine and other chemicals and asked whether or not they could stop a-synuclein misfolding.  Possibly a far-fetched  idea, 2 of the caffeine-double-headed compounds worked.  These studies used a novel a-synuclein-fluorescent-green substance expressed in yeast.  Expression of the green-a-synuclein misfolded and killed the yeast; however, in the presence of the caffeine-adducts, the green-a-synuclein folded properly and the yeast stayed alive.  Such cool science.  To read this paper, click here) “Novel dimer compounds that bind α-synuclein can rescue cell growth in a yeast model overexpressing α-synuclein. a possible prevention strategy for Parkinson’s disease”, Jeremy Lee et al., ACS Chem Neurosci. Epub 2016 Oct 7. 2016 Dec 21;7(12):1671-1680. doi: 10.1021/acschemneuro.6b00209.

“Autumn is my favourite season of all. It is a transitory period that allows the earth to rest before it sees the harshness of winter and hears the promise of spring.”  Kamand Kojouri

November, 2016: PINK1 gene mutation linked to early onset of Parkinson’s.  A single mutation in the PTEN-induced putative kinase 1 (PINK1) gene has been found to promote  the development of early-onset Parkinson’s. There is growing evidence that PINK1 collaborates with the protein named PARKIN; together they help regulate neuronal cell mitochondria. This interaction to regulate mitochondria (the cell’s power plant) by  PINK1 and PARKIN is important because many brain disorders are known to have issues with energy production (mitochondria) besides Parkinson’s. Click here to view paper: Puschmann, A., et al. Heterozygous PINK1 p.G411S increases risk of Parkinson’s disease via a dominant-negative mechanism. Brain 2016; 140 (1): 98-117. doi: 10.1093/brain/aww261.

“October extinguished itself in a rush of howling winds and driving rain and November arrived, cold as frozen iron, with hard frosts every morning and icy drafts that bit at exposed hands and faces.”  J.K. Rowling, Harry Potter and the Order of the Phoenix

December, 2016:  President Obama signed the 21st Century Cures Act. Not a paper but a National Institute of Health (NIH) federally-supported research initiative. The Cures Act is focused on  cancer, brain disease, drug addiction and other diseases/processes for the next  decade. The 21st Century Cures Act contains $4.8 billion in new NIH (National Institutes of Health) funds, including the BRAIN Initiative for the comprehensive mapping of  the brain.  It is anticipated that we will achieve an even better understanding of Parkinson’s than we have today.  Recently, a commentary about the Cures Act from the viewpoint of the NIH was published in the New England Journal of Medicine. Click here to read this article: Hudson, K. L. and F. S. Collins (2017). “The 21st Century Cures Act — A View from the NIH.” New England Journal of Medicine 376(2): 111-113.

“December’s wintery breath is already clouding the pond, frosting the pane, obscuring summer’s memory…” John Geddes

“I like the scientific spirit—the holding off, the being sure but not too sure, the willingness to surrender ideas when the evidence is against them: this is ultimately fine—it always keeps the way beyond open—always gives life, thought, affection, the whole man, a chance to try over again after a mistake—after a wrong guess.”  Walt Whitman, Walt Whitman’s Camden Conversations

Useful Parkinson’s disease News/Health Information/Reference Sites (click on links below):
Google Scholar- Parkinson’s disease
Parkinson’s News Today Weekly Digest
Medical News Today (MNT)
Science News- Mind & Brain News
Harvard Medical School- Harvard Healthbeat
The Science of Parkinson’s disease
STAT
NY Times- Well
Neurology Advisor

Cover photo credit: winter smoky mts- http://holicoffee.com/wp-content/uploads/2015/05/great-smoky-mountains-national-park-usa-extreme-out-door-hiking-trail-adventure-37.jpg

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Importance of Model Systems in Parkinson’s Research

“Science is organized knowledge. Wisdom is organized life.” Will Duran

“The most exciting phrase to hear in science, the one that heralds new discoveries, is not ‘Eureka!’ but ‘That’s funny…’” Isaac Asimov

Introduction:  The goal of this post is to highlight several experimental model systems that have effectively been used in Parkinson’s research.  We  have gained tremendous knowledge about all aspects of Parkinson’s from the use of model systems (Please note there are many publications that could have been included here by many different outstanding scientists; this is just a sampling of the strong science in the field of Parkinson’s disease).

The alpha-synuclein story in Parkinson’s: Alpha-synuclein is  a protein found in the brain that form aggregates (clumps of protein) called Lewy bodies.   Lewy bodies accumulate inside the substantia nigra region of the brain and they are toxic to the neurons and they no longer synthesize dopamine.   Part of the toxicity of alpha-synuclein-forming Lewy bodies is linked to mitochondria inhibition,  the little energy factories found in  our cells. This is just a sampling of alpha-synuclein in Parkinson’s (here is a PubMed search: http://www.ncbi.nlm.nih.gov/pubmed/?term=alpha-synuclein+Parkinson%27s ).

“Science is the process that takes us from confusion to understanding…” Brian Greene

The need for experimental model systems:  Scientists develop and use various experimental tools to answer their research questions. The ‘strength’ of the observation is usually dependent on the ‘quality’ of the experimental model system. Described here are four of many different experimental model systems: yeast; Caenorhabditis elegans (C. elegans); human, rat or mouse neuronal cells; and the mouse (or rat). Ultimately, scientists and physicians ‘translate’ this information for use in human clinical trials, which defines the phrase “bench-to-bedside”.

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“I never guess. It is a capital mistake to theorize before one has data. Insensibly one begins to twist facts to suit theories, instead of theories to suit facts.” Sir Arthur Conan Doyle, Author of Sherlock Holmes stories

Advancing our understanding of Parkinson’s using experimental model systems: You must remember a couple of things about science and research in general. Asking and answering one question usually leads to another question that needs to be answered. Typically, the next questions are more complex as the story unfolds. It is kind of like peeling an onion, you start taking off the top layer and you keep going; the more questions you answer the more layers you have to peel. Let’s go peel some onions.

Rising yeast in biology:  In our everyday lives,  baker’s yeast is used to make bread and alcoholic beverages like beer.  Yeast are single cell organisms, but like human cells they are eukaryotic (defined as “…cells that contain a distinct membrane-bound nucleus and by the occurrence of DNA transcription inside the nucleus and protein synthesis in the cytoplasm….” http://www.thefreedictionary.com/eukaryote ). Yeast are easy to culture and they share many similarities to human cells;  furthermore, genetic manipulation is relatively easy to do in yeast and offers a powerful tool for biomedical science. [Also see http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3213361/%5D

Use of yeast in Parkinson’s research Tardiff and others performed a really clever experiment, they expressed alpha-synuclein in yeast.  They found that yeast, just like human neuronal cells, got sick in the presence of excess amounts of alpha-synuclein.  They used the yeast expressing alpha-synuclein  and asked the following questions. Could a compound neutralize or reverse the alpha-synuclein-induced toxicity in yeast? Would this compound be able to restore normal function to the yeast?  They tested  ~190,000 compounds to see whether any of those would reverse the toxic effects and allow the yeast to rapidly grow again.  One lead compound evolved from this study, N-aryl benzimidazole (NAB).  NAB corrected the problem in yeast expressing alpha-synuclein. Using elegant genetics, they found that NAB activates a “trafficking” protein named Rsp5. The alpha-synuclein-induced toxicity  was inhibiting the function of Rsp5, which means that NAB reverses this effect. This sets the scene for new pathways to be explored for how Parkinson’s evolves, and presents a new strategy for exploring drugs to treat this disorder.
Tardiff DF, Jui NT, Khurana V, et al. Yeast reveal a “druggable” Rsp5/Nedd4 Network that Ameliorates α–Synuclein Toxicity in Neurons. Science (New York, NY). 2013;342(6161):979-983. doi:10.1126/science.1245321.

“Science is a way of thinking much more than it is a body of knowledge.” Carl Sagan

“Worm people” advancing science using C. elegans: C. elegans are non-parasitic soil nematodes that are free-living (…worms of the phylum Nematoda, having unsegmented cylindrical bodies often narrowing at each end, and including free-living species that are abundant in soil and water, and species that are parasites of plants and animals…” http://www.thefreedictionary.com/nematode ). C. elegans is a model organism due to its ability to be easily grown and manipulated genetically, which scientists use to advance complex biological principles.  [Also see http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1855192/%5D

Use of worms in Parkinson’s research Advanced age is the greatest known risk factor for development of Parkinson’s.  Why this happens is not fully understood. Cooper and others proposed the following hypothesis: “…there are specific changes that take place during the aging process that make cells susceptible to disease-causing mutations that are well-tolerated at younger ages.” To begin to ‘test’ this hypothesis, they used genetics and C. elegans as a model system.  Worms containing mutations in the daf-2 gene live twice as long as control worms.  The researchers crossed  C. elegans models of Parkinson’s with daf-2 mutants.  Compared to the appropriate control worms, the Parkinson’s/daf-2 mutant worms had longer lifespan, protection of dopamine neurons, resistance to inflammatory stress, and decreased Lewy-body formation. This C. elegans genetics-aging study implies that slowing down the aging process is neuroprotective in Parkinson’s.
Jason F Cooper, Dylan J Dues, Katie K Spielbauer, Emily Machiela, Megan M Senchuk, and Jeremy M Van Raamsdonk. Delaying aging is neuroprotective in Parkinson’s disease: a genetic analysis in C. elegans models. npj Parkinson’s Disease (2015) 1, 15022; doi:10.1038/npjparkd.2015.22; published online 19 November 2015

“What we find changes who we become.” Peter Morville

Cells provide a cultivating environment to model tissues/organs:  Over the past several decades, many different types of cells have been grown in sterile plastic dishes; ranging from “primary” cell extracts obtained from different organs to “immortalized” cell types from various tumor types (i.e., cancer).  Cells grown in vitro (defined as “performed or taking place in a test tube, culture dish, or elsewhere outside a living organism” https://www.google.com/search?q=define+in+vitro&ie=utf-8&oe=utf-8) do not fully recapitulate the organ of origin; nonetheless, cell culture is a powerful model system to study both normal biological and abnormal pathological processes. [Also see http://www.biologyreference.com/Bl-Ce/Cell-Culture.html%5D

Use of neuronal cells in Parkinson’s research Proteins have unique three-dimensional shapes, which encode their biological activity.  Sometimes, proteins go bad and do things that are pathological like alpha-synuclein forming aggregates. Moree and others are testing a hypothesis that small molecules can be discovered that reverse such detrimental protein aggregation. They developed a novel screening technique to identify compounds that modulate protein conformation (which is way beyond the scope of this blog posting). They discovered a compound named BIOD303 as a novel conformational modulator of alpha-synuclein.Interestingly, these modulators reduced alpha-synuclein aggregation in an experimental neuronal cell model. This sort of study could (possibly one day) lead to a novel process for treating Parkinson’s by reversing alpha-synuclein aggregates.
Moree B, Yin G, Lázaro DF, et al. Small Molecules Detected by Second-Harmonic Generation Modulate the Conformation of Monomeric α-Synuclein and Reduce Its Aggregation in Cells. The Journal of Biological Chemistry. 2015;290(46):27582-27593. doi:10.1074/jbc.M114.636027.

“Science does not know its debt to imagination.” Ralph Waldo Emerson

The mouse (rat) provides a most important model system:  Our understanding of many human diseases (think cardiovascular, cancer, and yes, Parkinson’s) has been advanced using mice and rats as model systems. One reason why mice are used is the similarity of mouse and human genetics. Scientists have done amazing feats using mice including “gene knockout” where specific genes have been deleted or inactivated.  Another type of mouse genetically-derived is the “transgenic mice”, which usually express genes thought to promote human diseases.  Ultimately, a mouse (or rat) with a specific disease becomes a model or ‘stand-in’ for that same human disease or condition.  [Also see  http://emice.nci.nih.gov/aam%5D

Use of rats in Parkinson’s researchVolakakis and others studied how alpha-synuclein promotes changes in dopamine-producing neurons. They found that alpha-synuclein alters gene expression and that a transcription factor (a protein that binds to specific DNA sequences that modulates the genetic information being transcribed from DNA to messenger RNA) known as Nurr1 helps resist these effects. They found that nuclear substances that bind to Nurr1’s partner retinoid X receptor (RXR) also had a neuroprotective role. Their results clearly highlight Nurr1’s neuroprotective role against alpha-synuclein-induced changes in dopamine-producing neurons. Furthermore, their results imply that RXR ligands have therapeutic potential in Parkinson’s.
Volakakis N, Tiklova K, Decressac M, Papathanou M, Mattsson B, Gillberg L, Nobre A, Björklund A, Perlmann T. Nurr1 and Retinoid X Receptor Ligands Stimulate Ret Signaling in Dopamine Neurons and Can Alleviate α-Synuclein Disrupted Gene Expression. J Neurosci. 2015 Oct 21;35(42):14370-85. doi: 10.1523/JNEUROSCI.1155-15.2015. PMID:26490873

“Barry L. Jacobs and colleagues from the neuroscience program at Princeton University showed that when mice ran every day on an exercise wheel, they developed more brain cells and they learned faster than sedentary controls. I believe in mice.”  Bernd Heinrich

From bench-to-bedside: The four papers described here represent the tip-of-the-iceberg in Parkinson’s research. As with any basic science study, the next step, the next few years are key to developing/advancing/evaluating these questions and getting answers. I am optimistic that new compounds, new treatment strategies, and further understanding of Parkinson’s are coming in the near future. It just will take time, so we must remain patient while all of their research endeavors progress.

“From the standpoint of daily life, however, there is one thing we do know: that we are here for the sake of each other – above all for those upon whose smile and well-being our own happiness depends, and also for the countless unknown souls with whose fate we are connected by a bond of sympathy. Many times a day I realize how much my own outer and inner life is built upon the labors of my fellow men, both living and dead, and how earnestly I must exert myself in order to give in return as much as I have received.” Albert Einstein

Cover photo credit: http://www.boredpanda.com/beautiful-winter-photos/

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