Parkinson's disease (PD) is a progressive neurodegenerative disease affecting millions of people. Synaptic dysfunction is an early event in the pathogenesis of the disease occurring prior to the onset of symptoms. Therapeutic interventions at these early stages hold the promise of slowing or even halting the disease. The biggest obstacle to the development of such therapies is a lack of knowledge of early molecular and synaptic events that occur in PD. Therefore, our long term objective is to understand the mechanisms of synaptic dysfunction in PD. a-Synuclein was the first gene identified to cause dominant familial PD, and is also the major constituent of Lewy bodies, the pathological hallmarks of PD. Hence, considerable effort is being directed at understanding the role of a-synuclein in the pathogenesis of PD. However, these efforts are focused mostly on toxic gain-of- function approaches, such as its aggregation. In contrast, little is known about the normal physiological functions of a-synuclein at the presynaptic terminal and its contribution to PD. This is the objective of our proposal. We have generated a novel mouse that lacks all synucleins to facilitate these studies. To attain the objective of this application, three aims are pursued. First, the interaction of synucleins with newly identified physiological partners and the bilayer will be examined. Second, the synaptic transmission deficits of synuclein null neurons will be characterized in culture and in vivo. Third, we will study how PD mutations impact these physiological properties and functions. Achieving these goals is important for human health, given aging demographics and the increasing prevalence of neurodegenerative diseases.

Public Health Relevance

a -Synuclein is a protein that forms clumps in the brains of Parkinson's patients. We are investigating what the normal function of a-synuclein is in the brain and whether alterations of this function plays a part in Parkinson's disease. This study will allow us, in time, to design early therapies for preventing cell death in Parkinson's disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Sieber, Beth-Anne
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Schools of Medicine
New Haven
United States
Zip Code
Vargas, Karina J; Schrod, Nikolas; Davis, Taylor et al. (2017) Synucleins Have Multiple Effects on Presynaptic Architecture. Cell Rep 18:161-173
Taguchi, Yumiko V; Liu, Jun; Ruan, Jiapeng et al. (2017) Glucosylsphingosine Promotes ?-Synuclein Pathology in Mutant GBA-Associated Parkinson's Disease. J Neurosci 37:9617-9631
Henderson, Michael X; Wirak, Gregory S; Zhang, Yong-Quan et al. (2016) Neuronal ceroid lipofuscinosis with DNAJC5/CSP? mutation has PPT1 pathology and exhibit aberrant protein palmitoylation. Acta Neuropathol 131:621-37
Zhang, Yong-Quan; Chandra, Sreeganga S (2014) Oligomerization of Cysteine String Protein alpha mutants causing adult neuronal ceroid lipofuscinosis. Biochim Biophys Acta 1842:2136-46
Vargas, Karina J; Makani, Sachin; Davis, Taylor et al. (2014) Synucleins regulate the kinetics of synaptic vesicle endocytosis. J Neurosci 34:9364-76
Westphal, Christopher H; Chandra, Sreeganga S (2013) Monomeric synucleins generate membrane curvature. J Biol Chem 288:1829-40
Zhang, Yong-Quan; Henderson, Michael X; Colangelo, Christopher M et al. (2012) Identification of CSP? clients reveals a role in dynamin 1 regulation. Neuron 74:136-50
Anwar, Sabina; Peters, Owen; Millership, Steven et al. (2011) Functional alterations to the nigrostriatal system in mice lacking all three members of the synuclein family. J Neurosci 31:7264-74
Greten-Harrison, Becket; Polydoro, Manuela; Morimoto-Tomita, Megumi et al. (2010) ???-Synuclein triple knockout mice reveal age-dependent neuronal dysfunction. Proc Natl Acad Sci U S A 107:19573-8