Leucine-rich Repeat Kinase 2 (LRRK2) Is A Possible Target For Therapy In Parkinson’s

“Research is the process of going up alleys to see if they are blind.”  Marston Bates

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

The reality of Parkinson’s: Parkinson’s is a common neurodegenerative disorder. Approximately 60,000 new cases/year of Parkinson’s occur in the USA, and they join ~1 million people living here with this disorder.  Life expectancy between the general population and patients with Parkinson’s are very similar. A public health study found that those who lived with Parkinson’s for 15-20 years had only a slightly shorter life expectancy than the general population without the disorder.  Knowledge and information about Parkinson’s is moving forward at a sustained pace.  We know a lot, really we do; however, there are still gaps in our understanding.

Mind-The-Gap1-300x253“Mind the gap”: The progress toward delineating the story of Parkinson’s is clearly going in the right direction.  For many though, the gaps are difficult to comprehend; it would be similar to reading a sentence with only three-fourth of the alphabet available. Please try to read the following sentence:
W hav mad trmndus advacs tratg smptms of Parknsn’s, altug a cur or owing nurodgnrtn s nt yt a ralty.
Now add back the missing letters, it reads as follows:
We have made tremendous advances treating symptoms of Parkinson’s, although a cure or slowing neurodegeneration is not yet a reality.

A new gap may have been filled, a possibility for a new target for therapy: As a scientist with Parkinson’s, I can sense the frustration with the public’s patience with the rate of advancing knowledge to curing this disorder.  However, my scientific training is in sheer awe of the real advances occurring in research laboratories and medical clinics dealing with new treatment strategies and the unraveling of the molecular details of Parkinson’s.

Scientists at University of Alabama at Birmingham (UAB) published a very nice article describing a small molecule (drug) that inhibits the mitochondrial enzyme with the catchy name of “leucine-rich repeat kinase 2″ (LRRK2, pronounced “lark two”).  What is LRRK2 (i.e., lark two) and how does this relate to Parkinson’s?

The Scorecard for LRRK2 and Parkinson’s:
•Scientists have discovered several Parkinson’s-causing genes mostly in early-age onset forms; strongly linking a genetic component to the cause of this disorder.
•Interestingly, mutations have been found in the LRRK2 gene in patients classified with typical ‘sporadic’ Parkinson’s ( 60-70 years old at diagnosis); resulting in a paradigm shift linking a possible genetic cause of the more typical form of Parkinson’s.
•Some Parkinson’s cases have a specific mutation in LRRK2 at amino acid residue 2019, termed G2019S, which ‘turns-on’ the kinase activity of LRRK2; this indicates that increased activity of LRRK2 G2019S plays a role in progression of the disorder.
•The LRRK2-G2019S mutation has been found as a common cause of Parkinson’s: ~5–6% of familial Parkinson’s and ~1–2% of sporadic Parkinson’s in the USA and several European populations.
•As described here before, the protein α-synuclein is linked both in the human disorder and in animal models of Parkinson’s (https://journeywithparkinsons.com/2015/06/21/of-mice-and-men-endogenous-alpha-synuclein-contributes-to-mitochondria-inhibition-in-parkinsons/ and https://journeywithparkinsons.com/2015/05/23/the-alpha-synuclein-story-in-parkinsons/ ).
•The UAB group showed that rats deficient in LRRK2 (“gene knockout”) were protected from neurodegeneration in the α-synuclein-overexpression rat model; these results imply a role for LRRK2 in the progression of Parkinson’s.
•They next used rats that were making human G2019S-LRRK2 in the human α-synuclein-over-expressing rat model (in the substantia nigra). Rats were fed a drug for four weeks that was a specific LRRK2 inhibitor.  Compared to control rats not fed this novel drug, test rats were protected from neurodegeneration.
•The small-molecule inhibitor made its way from the gut to the bloodstream and then through the blood-brain barrier to reach the brain and the substantia nigra.
•To read this paper by João Daher and others entitled “LRRK2 Pharmacological Inhibition Abates α-Synuclein Induced Neurodegeneration” ( jbc.M115.660001) go here: http://www.jbc.org/content/early/2015/06/15/jbc.M115.660001.full.pdf+html
The drawing below is an attempt to depict the small-molecule inhibitor (drug) to prevent neurodegeneration in the rat model expressing human LRRK2 and α-synuclein to promote Parkinson’s.


Hope for LRRK2 as a target for therapy in Parkinson’s: There are currently no effective therapies to halt the progression of Parkinson’s; thus, clearly this is part of the “Holy Grail” of Parkinson’s research. The UAB group states: “For a patient with disease onset in the mid-60s, Parkinson’s disease runs its course over 10 to 15 years. So, if we can slow down the disease by even 50 percent, that may be effectively as good as a cure, given the available symptomatic treatments.”  However, the authors of this work are realistic in linking the rat model to the human disorder: “We have to be very careful with what our models can tell us.  We need to think critically about what type of benefit we can expect to see in humans because there are recent examples where improper clinical trial design have hindered the development of a new class of drugs for years and sometimes decades.”

There is real hope for slowing the progression of Parkinson’s. The research being performed on Parkinson’s all-over-the-world leaves me hopeful for new strategies to this disorder.  New ideas by good scientists have us on a hopeful path. And yes, I’m convinced these types of novel findings will eventually (sadly, years from now) begin to benefit humans with Parkinson’s.

“The way to do research is to attack the facts at the point of greatest astonishment.”  Celia Green

Citations used and for additional information:
http://www.jbc.org/content/early/2015/06/15/jbc.M115.660001 ;
http://www.uab.edu/news/innovation/item/6225-potential-drug-lessens-neurodegeneration-in-parkinson-s-disease-model ;
https://thehealtharchive.wordpress.com/2015/06/27/%CE%B1-synuclein-and-lrrk2-used-to-lessen-neurodegeneration-parkinsons-disease/ ;
https://www.michaeljfox.org/understanding-parkinsons/living-with-pd/topic.php?lrrk2 ;
Genetic characteristics of leucine-rich repeat kinase 2 (LRRK2) associated Parkinson’s disease: http://www.ncbi.nlm.nih.gov/pubmed/21641266 .

Cover photo credit: http://img2.goodfon.su/original/2560×1700/5/5f/palm-beach-florida-palm-bich.jpg

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