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.
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
- Vargas, K.J., Makhani, S., Davis, T., Westphal, C., Castillo, P.E., and Chandra, S.S. (2014). Synucleins regulate the kinetics of synaptic vesicle endocytosis. J. Neuroscience. 34, 9364-9376. Cover Article
- Vargas, K.J., and Chandra, S.S. (2014). Synucleins. In Michael Caplan (Ed.), Reference Module in Biomedical Sciences, Elsevier, Oxford. In Press.
- Westphal, C. and Chandra, S. (2013). Synucleins generate membrane curvature. J. Biol. Chem. 288, 1829-1840. PMID: 23184946
- Zhang, Y., Henderson, M.X., Colangelo, C.M., Ginsberg, S., Bruce, C., Terence Wu, T., Chandra, S. (2012). Identification of CSPalpha clients reveals a role in dynamin 1 regulation. Neuron. 74, 136-150.
- Greten-Harrison, B., Polydoro, M., Tomita, M., Diao, L., Williams, A.M., Nie, E.H., Makani, S., Tian, N., Castillo, P.E., Buchman, V.L., and Chandra, S. (2010). Alpha beta gamma-Synuclein Triple Knockout Mice Reveal Age-Dependent Neuronal Dysfunction.
- Chandra, S., Gallardo, G, Fernandez-Chacon, R., Schlueter, O.M. (2005) Alpha-Synuclein cooperates with CSP-alpha in preventing neurodegeneration, Cell, 123, 383-396