Udall Center - The Brigham and Women’s Hospital

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Director: Jie Shen, Ph.D.

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

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

Central Theme

The BWH Udall Center brings together a group of basic neuroscientists who are dedicated to the investigation of the pathogenic mechanisms of Parkinson’s disease (PD) and clinicians who are dedicated to the treatment of PD patients and improving the quality of their lives. The primary goal of this Udall Center is to advance PD research through investigation of two major PD genes, α-synuclein and LRRK2, in disease pathogenesis. There are three Research Projects and one Research Core with a central theme on autophagy, which is a major protein degradation pathway that often goes awry in neurodegenerative disease, as α-synuclein is degraded through this pathway and LRRK2 is an essential regulator. We will investigate how α-synuclein mediates its neurotoxicity in mouse and human neurons (Tom Südhof), how genetic defects in LRRK2 cause PD and whether α-synuclein mediates LRRK-dependent survival of dopamine (DA) producing neurons (Jie Shen), and how LRRK2 regulates autophagy pathways and α-synuclein homeostasis (Zhenyu Yue). Two other major missions of the BWH Udall Center are the training of independent and competent next generation PD researchers and service as local resources for PD patient community, which are headed by Training Director, Mel Feany, and public Outreach Director, David Simon, respectively.

Center Structure

The BWH Udall Center brings together three investigators, Drs. Tom Südhof, Jie Shen and Zhenyu Yue, whose complementary expertise and research interests on a-synuclein and LRRK2 will facilitate 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 an Administrative and Outreach Core. Project 1 (Dr. Südhof) uses mouse models of synucleins and human induced pluripotent stem (iPS) cell-derived neurons to investigate the mechanism underlying α-synuclein neurotoxicity. Project 2 (Dr. Shen) 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. Project 3 (Dr. Yue) investigates the molecular mechanisms by which LRRK regulates autophagy pathways and α-synuclein homeostasis.

Recent Advances

Project 1 (Dr. Südhof): Using compound transgenic/KO mice that are α- b- and g-synuclein triple knockout mice and express Thy1-ChR2-YFP and DAT-Cre, we used optogenetic tools to selectively activate corticostriatal and nigrostriatal projections. We used combined electrophysiology, cyclic voltammetry and optogenetics to investigate how loss of synuclein function affects normal synaptic transmission in these long-range projections. We have obtained mice from these crosses, and successfully obtained recordings from a small cohort of animals. We unexpectedly observed major changes in long-term plasticity in synuclein triple knockout mice that we are now following up. We have also started analyzing the human neuron mutants described in the application, and are at a first step in the process of validating them.

Project 2 (Dr. Shen): We have completed the analysis of LRRK1/2 double KO mice as well as LRRK1 and LRRK2 single KO mice, relative to wild-type controls, and found that inactivation of both LRRK1 and LRRK2 results in earlier mortality and age-dependent, selective neurodegeneration. Loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and noradrenergic neurons in the locus coeruleus is accompanied with increases in apoptosis, whereas the cerebral cortex and cerebellum are unaffected. Furthermore, selective age-dependent neurodegeneration is only present in LRRK-/- but not LRRK1-/- or LRRK2-/- brains, and is accompanied with increases of α-synuclein and impairment of the autophagy-lysosomal pathway. Quantitative electron microscopy analysis revealed age-dependent increases of autophagic vacuoles in the SNpc of LRRK-/- mice before the onset of dopaminergic neuron loss. These findings revealed an essential role of LRRK in the survival of dopaminergic neurons and the regulation of the autophagy-lysosomal pathway in the aging brain.

Project 3 (Dr. Yue): We have established germline deletion of ULK1 in mice and are currently crossing them to LRRK2 transgenic mice. Our whole proteome and phosphor-proteome analysis in LRRK2 BAC and KO mice revealed that autophagy pathway is likely to be regulated by LRRK2 mutants.  Finally, we have performed studies in cultured neurons and microglial cells to assess the role for autophagy in regulating a-synuclein clearance. Our preliminary results show that microglia employ canonical autophagy pathways to clear a-synuclein.

Public Health Statement

The BWH Udall Center addresses a pressing public health need to better understand the underlying causes of Parkinson’s Disease (PD). We employ state-of-the art, complementary multidisciplinary approaches to investigate how mutations 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 science, molecular pathways, multifaceted and multidisciplinary approaches from mouse neurons to brains to human neurons, and from biochemical and cell biological techniques to genetics, imaging, electrophysiology and mouse behavior.

Budget End Date: 2020/06/30

NIH Grant Number:  P50 NS094733