ROAD TO THE CURE UPDATE NOVEMBER 2014 · Parkinson's Resource Organization

ROAD TO THE CURE UPDATE NOVEMBER 2014

Category: Road to the Cure

Making history, the PARKINSON’S ROAD TO THE CURE continues ….. LRRK2 and the Parkinsons Connection.

Parkinson’s disease is a gradually progressing disorder of the nervous system that causes stiffness or slowness of movement. Currently, as many as 1.1 million Americans are living with the disease. Globally, this number is in excess of 10 million. An estimated 10 percent of Parkinson’s disease cases so far have been linked to a genetic cause. Unfortunately, Ashkenazi Jewish and North African Arab Berbers represent two particular ethnic backgrounds in which mutations in LRRK2 account for a much greater number of Parkinson’s disease cases than in the general population.

According to some statistics, it is believed that mutations in LRRK2, predominantly the mutation known as G2019S, account for 15 to 20 percent of Parkinson’s disease cases in Ashkenazi Jews and about 40 percent of the cases in North African Arab Berbers. Other genetic changes in LRRK2 that increase the risk of Parkinson’s disease have been found in additional populations, such as in the Asians of Chinese descent. It remains an active area of investigation to find all the genetic changes in LRRK2 that may lead to Parkinson’s disease.

How do LRRK2 mutations cause Parkinsons disease? The LRRK2 gene is active in the brain and other tissues throughout the body. The normal function of LRRK2 protein is to assist in the transfer of a phosphate group from the energy molecule adenosine-triphosphate (ATP) to amino acids in certain proteins. This phosphate transfer is called phosphorylation, and it is an essential step in turning on and off many cell activities. In other words, LRRK2 has kinase activity, which means an ability to add a phosphate group onto proteins.

However, mutated LRRK2 results in over phosphorylation of proteins or over-manufacturing of phosphorylated proteins, which the neurons cannot process effectively, leading to accumulation of unprocessed phosphorylated proteins. An excess of these proteins leads to the death of dopamine producing neurons in the brain. The evidence that G2019S mutation is pathogenic is overwhelming. This mutation is very frequent in Parkinson’s patients and extremely rare in healthy controls.

How to develop a drug for Parkinsons patients carrying a mutant LRRK2 Gene? In general, it is difficult to develop inhibitors (drugs) for proteins/enzymes with kinase (phosphorylation) activity. The conventional approach has been to design and synthesize thousands of small organic compounds and screen them for their kinase activity inhibition property, a process that is very cumbersome and expensive involving decades of time, with no guarantee of success. However, with adequate resources, persistence and some good luck, scientists can develop a drug for controlling the kinase activity of mutant LRRK2 but so far such a drug does not exist.

Due to the small number of patients whose disease is linked to mutations in the LRRK2 gene, big pharmaceutical companies are not dedicating resources to develop inhibitors for aberrant kinase activity of LRRK2. Due to their large size, classical heterotetrameric antibodies usually cannot grab onto the small active site on the protein kinases such as LRRK2 protein. However, our novel antibody mimics, known as SMART Molecules, have unique characteristics and ability to bind to the active sites on the protein kinases. So, the potential that our SMART Molecules can provide a Parkinson’s curing drug is very high. Unfortunately, this high potential is marred by the exorbitant cost of mutant LRRK2 protein. ICBI needs a minimum of 50 mg of this protein. Invitrogen, also known as, Life Technologies, is selling this protein. The cost of 50 mg will be $472,500. Raising an adequate amount of funds is needed, so that developing a drug for controlling the function of mutant LRRK2 becomes a reality.

In April we proudly introduced the scientists and their incomparable history making work on the PARKINSON’S ROAD TO THE CURE. This remarkable science continues as they provide the relationship with Parkinson’s disease and LRRK2 and continue reporting their progress. We invite you to contact us or them if you want information about supporting or investing in The Parkinsons Road to the Cure. We would be proud to make this important introduction and we continue to salute our scientists as they forge ahead!    

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Updated: August 16, 2017