“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
“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).
“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.
- 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
Featured cover image credit: https://www.pinterest.com/pin/22025485657771738/?lp=true