Grant: CIHR Fellowship

Parkinson disease (PD) is a common neurodegenerative disorder affecting movement and cognition. The greatest burden is to patients and families, affecting over 100,000 Canadians with >2.5 billion dollars. The main drug treatment is L-dopa which helps the motoric symptoms but fails to halt the progression of disease. Development of treatment to halt disease progression has been limited. The most common pathogenic mutation that causes sporadic and familial PD is LRRK2 (Leucine-rich repeat kinase 2) p.G2019S. LRRK2 mutations accounts for up to 40% of sporadic PD in Tunisia. However, the penetrance of LRRK2 p.G2019S is highly variable. Given the relatively high rate of occurrence of LRRK2 mutations, finding markers for and elucidating mechanisms of reduced penetrance has a high imperative. I have previously identified DNM3 (Dynamin 3) as a potential genetic modifier of disease penetrance in LRRK2 p.G2019S carriers. I now hypothesize that biological mechanisms including dynamin-related proteins can modulate the phenoconversion of LRRK2 p.G2019S and the identification of these mechanisms will provide insight for developing treatments for patients. We propose that there are large genetic and biological influences that explain the differences in age-at-onset in families with LRRK2 p.G2019S. We will select skin cells from specific individuals to make induced pluripotent stem cells (IPSCs) to differentiate into human neurons. Molecular, cellular and physiological studies of LRRK2 p.G2019S human will be characterized at a high-throughput 'omics' level.