The BWH Udall Center brings together three accomplished investigators, Tom Südhof, Jie Shen and Zhenyu Yue whose complementary expertise and research interests on α-synuclein and LRRK2 will facilitate the discovery on how mutations in these dominant PD genes lead to age-dependent degeneration of DA neurons and α-synuclein aggregation. The Center is comprised of three inter-related, complementary Research Projects, one Research Core and Administrative and Outreach Core. Our Udall Center will be governed through the Executive Committee, the Internal Advisory Committee and the External Advisory Committee.
Project 1: Mechanism of α-synuclein neurotoxicity
Principal Investigator/Project Lead: Tom Südhof, Stanford University
α-Synuclein physiologically functions as a non-classical chaperone that enhances SNARE-complex assembly during synaptic vesicle exocytosis, but pathologically misfolds into a toxic conformer in PD and other synucleinopathies. Experimental evidence suggests that α-synuclein and LRRK2 are closely linked through the autophagy-lysosomal pathway. However, the mechanism of α-synuclein neurotoxicity, the relation of α-synuclein neurotoxicity to LRRK2 and autophagy, and their collaborative role in PD-related neurodegeneration remain unclear. Furthermore, non-DA neurons are affected in PD and other synucleinopathies. Based on these observations, Project 1 proposes two Aims to investigate the general mechanism of α-synuclein neurotoxicity in non-DA and DA neurons, and to determine the relation of the pathophysiological and normal physiological function of α-synuclein using mouse and human neurons.
Project 2: Genetic interaction of LRRK2 and α-synuclein
Principal Investigator/Project Lead: Jie Shen, Brigham and Women’s Hospital
Dominantly inherited mutations in LRRK2 and α-synuclein are the most common genetic cause of PD. Our previous genetic analysis revealed an interesting interaction between these two dominant PD genes. During aging LRRK2 is an essential regulator of the autophagy-lysosomal pathway, and α-synuclein is a substrate, based on findings that LRRK2 inactivation results in bi-phasic alterations of autophagy activity and α-synuclein homeostasis, and increases of apoptosis in the kidney where LRRK2 is normally most highly expressed. We are the in the process of testing whether inactivation of both LRRK2 and its functional homolog LRRK1 causes age-dependent, selective loss of dopaminergic neurons as well as autophagy impairment and α-synuclein accumulation. Project 2 proposes two Aims to investigate the pathogenic mechanisms underlying LRRK2 mutations, and to explore the genetic interaction between LRRK2 and α-synuclein.
Project 3: Elucidating Autophagy-lysosome Mechanism in LRRK2 and α-synuclein Pathogenic Pathways
Principal Investigator/Project Lead: Zhenyu Yue, Icahn School of Medicine at Mount Sinai Hospital
Emerging evidence from the studies of PD genes, such as a–synuclein, LRRK2, Parkin, Pink1, GBA and ATP13A2, implicates a dysfunction of the autophagy-lysosomal pathway in the pathogenesis of PD. However, the molecular mechanisms by which disease mutations impair autophagy and cause neurotoxicity in PD remain elusive. Genetic studies of LRRK2 demonstrated a key role of LRRK2 in autophagy control. We recently found a direct link between LRRK2 and autophagy machinery proteins. We therefore propose two Aims to investigate the molecular mechanisms by which LRRK regulates autophagy pathways, and the mechanisms by which LRRK2 and autophagy modulate a-synuclein homeostasis.