- Friday, April 15, 2016
- 1:30 PM–2:30 PM
- Science Building 010
Darren Moore, Ph.D. Associate Professor, Center for Neurodegenerative Science Van Andel Institute
Parkinson's disease (PD) is a chronic neurodegenerative movement disorder of unknown etiology. While typically occurring as an idiopathic disease, 5-10% of PD is inherited in a familial manner. Today, mutations in at least eleven genes are known to unambiguously cause monogenic forms of PD, with either autosomal dominant (SNCA, LRRK2, VPS35, EIF4G1, DNAJC13) or recessive (PARK2, DJ-1, PINK1, ATP13A2, SYNJ1, DNAJC6) inheritance. Genome-wide association studies also implicate common variation in the SNCA and LRRK2 genes with an increased risk of developing idiopathic PD. Despite the preponderance of genetic evidence in explaining many cases of PD, the mechanism(s) by which mutations in each of these gene products precipitates selective neurodegeneration remains largely enigmatic. In most cases, the physiological function of these PD-associated proteins and the molecular basis of familial mutations remain obscure, whereas the anticipated interplay amongst these proteins in common pathological pathways leading to PD is poorly defined. In this talk, we describe our recent efforts in dissecting the molecular and cellular basis of mutations in the dominant PD gene product, LRRK2. We will describe the impact of familial mutations on the two enzymatic activities of this protein (i.e. kinase and GTPase), the intramolecular regulation of these activities, and how they contribute to neuronal toxicity. Furthermore, we will discuss the development of novel cellular and rodent models for exploring the pathogenic effects of LRRK2 and how we are beginning to utilize such models for the identification of key enzymatic activities, molecular targets and cellular pathways that are important for LRRK2-dependent neuronal damage. Our studies are important for the identification and validation of novel molecular targets and pathways that can be exploited for the development of new therapeutic agents to treat PD.