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Séminaire - Sreeganga CHANDRAThe Physiology and Pathology of alpha-Synuclein Reveals how Synaptic Dysfunction is Linked to Neurodegeneration

Abstract :

The majority of synapses are largely stable throughout the life of an organism to ensure normal brain functions and behaviors. However, in late-onset neurodegenerative disorders, synaptic dysfunction and synapse loss are early, pivotal events. In these devastating diseases, synaptic changes occur in the prodromal stage of disease, prior to neuronal cell death. Thus, elucidating the mechanisms by which synapses are maintained is of high biomedical relevance. Recent work, including from my group, has shown that local proteostasis mechanisms are essential for maintaining the structure and functionality of synapses. Emerging human genetic data strongly support the tenet that synaptic proteostasis is disrupted in late-onset neurodegenerative diseases. My group currently investigates two such diseases: Parkinson's disease (PD) and Neuronal Ceroid Lipofuscinosis (NCL).

 Our central hypothesis is that PD and NCL are diseases of presynaptic proteostasis and dysfunction.The findings that a-synuclein, a key protein in the pathophysiology of PD, oligomerizes at the presynaptic terminal and presynaptic co-chaperones, CSPaand auxilin are mutated in NCL and PD, respectively, strongly support our hypothesis. My research program has a record of innovative and productive contributions to this important area of cellular neuroscience. Our approaches include proteomics, in vivo studies of mouse models, and imaging of human-derived neurons. Our basic research  has immense potential for the development of disease modifying therapies for these diseases. 

Chandra Lab

Selected publications

Neuronal ceroid lipofuscinosis with DNAJC5/CSPα mutation has PPT1 pathology and exhibit aberrant protein palmitoylationHenderson MX, Wirak GS, Zhang YQ, Dai F, Ginsberg SD, Dolzhanskaya N, Staropoli JF, Nijssen PC, Lam TT, Roth AF, Davis NG, Dawson G, Velinov M, Chandra SS. Acta Neuropathol. 2016 Apr;131(4):621-37. doi: 10.1007/s00401-015-1512-2. Epub 2015 Dec 1

Biochim Biophys Acta. 2014 Nov;1842(11):2136-46. doi: 10.1016/j.bbadis.2014.07.009. Epub 2014 Jul 23. Oligomerization of Cysteine String Protein alpha mutants causing adult neuronal ceroid lipofuscinosis. Zhang YQ1, Chandra SS2.

J Neurosci. 2014 Jul 9;34(28):9364-76. doi: 10.1523/JNEUROSCI.4787-13.2014. Synucleins regulate the kinetics of synaptic vesicle endocytosis. Vargas KJ1, Makani S2, Davis T1, Westphal CH3, Castillo PE2, Chandra SS4.

Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3489-94. doi: 10.1073/pnas.1222732110. Epub 2013 Jan 28. Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration. Bilguvar K1, Tyagi NK, Ozkara C, Tuysuz B, Bakircioglu M, Choi M, Delil S, Caglayan AO, Baranoski JF, Erturk O, Yalcinkaya C, Karacorlu M, Dincer A, Johnson MH, Mane S, Chandra SS, Louvi A, Boggon TJ, Lifton RP, Horwich AL, Gunel M.

Scientific focus :

I am an Associate Professor in the Program in Cellular Neuroscience, Neurodegeneration and Repair (CNNR), Departments of Neurology, Neuroscience, and Molecular Cellular and Developmental Biology at Yale University. I did my postdoctoral training in the laboratory of Thomas Südhof, in synaptic biology and mouse genetics, with a focus on neurodegeneration.  The long-term goal of my lab's research is to define how synapses are normally maintained in the healthy brain and how disruption in these processes results in neurodegenerative disorders.