Research Departments & Organizations
Neurology: Chandra Lab
My lab explores two related themes, those of synapse loss and neurodegeneration. Synapse loss is an early, defining event in neurodegenerative diseases, such as Parkinson's disease. In these prolonged diseases, decreases in synapse density are the best correlates of disease progression.Yet, little is known about the pathways that maintain synapses and their roles in aging and neurodegeneration. We are characterizing a novel presynaptic mechanism for the prevention of synapse loss and neurodegeneration involving the co-chaperone Cysteine String Protein alpha. This gene is also mutated in adult-onset neuronal ceroid lipofuscinosis, a neurodegenerative disorder with lysosomal pathology. We are also screening for new synapse maintenance genes using a dissociated neuronal culture system.
Parkinson's disease (PD) is a prevalent, neurodegenerative disease with a strong genetic underpinnings. The first PD gene to be identified was the alpha-synuclein gene. Three point mutations and gene multiplications link alpha-synuclein to familial PD. In addition, alpha-synuclein protein is the main component of Lewy bodies, the pathological signature for PD. We are elucidating both the physiological functions and pathological properties of alpha-synuclein, in an effort to understand its central role in PD. Our lab uses mouse genetics in combination with biochemical, biophysical, and cell biological approaches to tackle these important questions.
- Presynaptic Biology
- Synapse Maintenance
- Parkinson's Disease
- Neuronal Ceroid Lipofuscinosis
Extensive Research Description
- Identification of the physiological function of synucleins
- Role of CSP alpha in synapse maintenance
- Identification of novel synapse maintenance genes
- Interplay between PARK genes
- Protein palmitoylation and neuronal ceroid lipofuscinosis
Synucleins regulate the kinetics of synaptic vesicle endocytosis.
Vargas KJ, Makani S, Davis T, Westphal CH, Castillo PE, Chandra SS. Synucleins regulate the kinetics of synaptic vesicle endocytosis. The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience 2014, 34:9364-76. 2014
Vargas, K.J., and Chandra, S.S. (2014). Synucleins. In Michael Caplan (Ed.), Reference Module in Biomedical Sciences, Elsevier, Oxford. In Press. 2014
Monomeric synucleins generate membrane curvature.
Westphal CH, Chandra SS. Monomeric synucleins generate membrane curvature. The Journal Of Biological Chemistry 2013, 288:1829-40. 2013
Identification of CSPα clients reveals a role in dynamin 1 regulation.
Zhang YQ, Henderson MX, Colangelo CM, Ginsberg SD, Bruce C, Wu T, Chandra SS. Identification of CSPα clients reveals a role in dynamin 1 regulation. Neuron 2012, 74:136-50. 2012
αβγ-Synuclein triple knockout mice reveal age-dependent neuronal dysfunction.
Greten-Harrison B, Polydoro M, Morimoto-Tomita M, Diao L, Williams AM, Nie EH, Makani S, Tian N, Castillo PE, Buchman VL, Chandra SS. αβγ-Synuclein triple knockout mice reveal age-dependent neuronal dysfunction. Proceedings Of The National Academy Of Sciences Of The United States Of America 2010, 107:19573-8. 2010
Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration.
Chandra S, Gallardo G, Fernández-Chacón R, Schlüter OM, Südhof TC. Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration. Cell 2005, 123:383-96. 2005