Udall Center - The Brigham and Women’s Hospital

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Director: Jie Shen, PhD

Title: ɑ-Synuclein and LRRK2 in the Pathogenesis of Parkinson’s Disease

Website: http://udallcenter.bwh.harvard.edu/

Budget End Date: 6/30/2020
 

Central Theme

The primary goal of the NINDS Udall Center at the Brigham and Women’s Hospital (BWH) is to advance Parkinson’s Disease (PD) research through investigation of the roles of two major PD risk genes, alpha (ɑ)-synuclein and LRRK2, in disease pathogenesis. The Center will focus on the role of autophagy, a major protein degradation pathway, in PD, as α-synuclein is degraded through this pathway and LRRK2 is an essential regulator of its function. Two additional goals of the BWH Udall Center are: to train the next-generation of PD researchers, and to serve as a local resource for PD patient community.

Center Structure

The BWH Udall Center brings together three accomplished investigators, Thomas Südhof, MD, PhD (Stanford University), Jie Shen, PhD (BWH) and Zhenyu Yue, PhD (Icahn School of Medicine at Mount Sinai), whose complementary expertise and research interests on ɑ-synuclein and LRRK2 will facilitate the discovery of 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 synergistic Research Projects, one Research Core and an Administrative and Outreach Core. Within the latter Core, Mel Feany, MD, PhD serves as the Training Director, and David Simon, MD, PhD serves as the Director of Public Outreach.

Research collaborations will investigate how α-synuclein mediates its neurotoxicity in mouse and human neurons (Südhof), how genetic defects in LRRK2 cause PD and whether α-synuclein mediates LRRK-dependent survival of dopamine producing neurons (Shen), and how LRRK2 regulates autophagy pathways and α-synuclein homeostasis (Yue).

Project 1, Mechanism of α-synuclein neurotoxicity (Thomas C. Südhof, MD) uses mouse models of synucleins and human induced pluripotent stem (iPS) cell-derived neurons to investigate the mechanism underlying α-synuclein neurotoxicity. 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-dopamine (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 (Jie Shen, PhD) investigates the pathogenic mechanism underlying LRRK2 mutations and the genetic interaction between α-synuclein and LRRK2 in the regulation of autophagy and DA neuron survival. 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 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 mechanisms in LRRK2 and α-synuclein pathogenic Pathways (Zhenyu Yue, PhD). Emerging evidence from the studies of PD genes, such as α-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 are pursuing two Aims to investigate the molecular mechanisms by which LRRK regulates autophagy pathways, and the mechanisms by which LRRK2 and autophagy modulate α-synuclein homeostasis.

Ongoing research at the BWH Udall Center addresses several NINDS PD2014 research priorities, including

  • Basic Research Recommendation 2: Elucidate the normal and abnormal function of α-synuclein and its relationship to other PD genes (e.g. ATP13A2, GBA, LRRK2, PINK1 and PARK2).
  • Basic Research Recommendation 4, Generate and characterize a panel of PD-specific iPS cells for “omic” pathway analysis and other approaches.
  • Basic Research Recommendation 10: Develop a more comprehensive understanding of the role of catabolic pathways in PD, including assessment of both the ubiquitin-proteasome and the autophagy-lysosomal systems.

Publications from the BWH Udall Center

Resources Available

The following mouse lines are available through Jackson Laboratories:

  • LRRK2 R1441C knockin mice
  • LRRK2-/- mice
  • Synuclein triple knockout mice and ɑ-synuclein transgenic mice
  • BAC transgenic LRRK2-G2019S and LRKR2-WT mice

Public Health Statement

The BWH Udall Center addresses a pressing public health need to better understand the underlying causes of Parkinson’s Disease (PD). The team employs state-of-the art research approaches to investigate how mutations (alterations) in two major PD risk genes, LRRK2 and α-synuclein, result in brain changes that cause PD. Our Center serves a unique niche in the NINDS Udall Center program with emphasis on basic disease-related brain research, using multiple approaches to understand how changes in genes result in changes in brain function that result in PD.

For further information: http://udallcenter.bwh.harvard.edu/contact/