Neurology; Neuronal Ceroid-Lipofuscinoses; Parkinson Disease; Synapses; Receptors, Presynaptic; Neurodegenerative Diseases
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, 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
- Synucleins Vargas, K.J., and Chandra, S.S. (2014). Synucleins. In Michael Caplan (Ed.), Reference Module in Biomedical Sciences, Elsevier, Oxford. In Press.
Synucleins generate membrane curvature
Westphal, C. and Chandra, S. (2013). Synucleins generate membrane curvature. J. Biol. Chem. 288, 1829-1840. PMID: 23184946
Identification of CSPalpha clients reveals a role in dynamin 1 regulation
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.
Alpha beta gamma-Synuclein Triple Knockout Mice Reveal Age-Dependent Neuronal Dysfunction
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.
Alpha-Synuclein cooperates with CSP-alpha in preventing neurodegeneration
Chandra, S., Gallardo, G, Fernandez-Chacon, R., Schlueter, O.M. (2005) Alpha-Synuclein cooperates with CSP-alpha in preventing neurodegeneration, Cell, 123, 383-396
Full List of PubMed Publications
- Gorenberg EL, Chandra SS: The Role of Co-chaperones in Synaptic Proteostasis and Neurodegenerative Disease. Front Neurosci. 2017; 2017 May 19. PMID: 28579939
- Vargas KJ, Schrod N, Davis T, Fernandez-Busnadiego R, Taguchi YV, Laugks U, Lucic V, Chandra SS: Synucleins Have Multiple Effects on Presynaptic Architecture. Cell Rep. 2017 Jan 3. PMID: 28052246
- Henderson 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: Neuronal ceroid lipofuscinosis with DNAJC5/CSPα mutation has PPT1 pathology and exhibit aberrant protein palmitoylation. Acta Neuropathol. 2016 Apr; 2015 Dec 10. PMID: 26659577
- Zhang YQ, Chandra SS: Oligomerization of Cysteine String Protein alpha mutants causing adult neuronal ceroid lipofuscinosis. Biochim Biophys Acta. 2014 Nov; 2014 Jul 23. PMID: 25064588
- Vargas KJ, Makani S, Davis T, Westphal CH, Castillo PE, Chandra SS: Synucleins regulate the kinetics of synaptic vesicle endocytosis. J Neurosci. 2014 Jul 9. PMID: 25009269
- Bilguvar K, 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: Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration. Proc Natl Acad Sci U S A. 2013 Feb 26; 2013 Jan 28. PMID: 23359680
- Westphal CH, Chandra SS: Monomeric synucleins generate membrane curvature. J Biol Chem. 2013 Jan 18; 2012 Nov 26. PMID: 23184946
- 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 Apr 12. PMID: 22500636
- 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. Proc Natl Acad Sci U S A. 2010 Nov 9; 2010 Oct 25. PMID: 20974939