Assistant Professor, Department of Neurology
Yale Program in Cellular Neuroscience,
Neurodegeneration and Repair

Yale School of Medicine
Department of Neurology
295 Congress Ave.
BCMM 154D
New Haven, CT 06536

Phone: 203.785.6172
Fax: 203.737.2267
Email: sreeganga.chandra@yale.edu

The adult human brain has billions of neurons, each making thousands of synapses with other neurons. In vertebrates, these synapses can be at great distances from the cell body, necessitating nerve terminals be functionally autonomous. Indeed, synapses can function at astonishing speeds and precision for extended periods of time in an autonomous fashion. This suggests that there are synaptic surveillance, repair and protection mechanisms that allow for continuous operation of nerve terminals. Are these mechanisms awry in aging and neurodegenerative diseases?

A growing body of evidence suggests that synapses are distinct degenerative compartments and that synapse loss is an early, fundamentally pathogenic event in neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease. In these prevalent diseases, decreases in synapse density are the best correlates of disease progression known to date. Significantly, these synaptic changes occur many years prior to irreversible neuronal cell death. Thus, loss of synaptic terminals is a harbinger for the neuronal death that is to ensue and affords a window for therapeutic interventions. Notably, in animal models for these neurodegenerative diseases, protection of synapses leads to sparing of neurons. Yet, little is known about the players involved in synapse maintenance and their role in aging and neurodegenerative diseases.

We are interested in addressing these questions regarding synapse autonomy, synapse maintenance and neurodegeneration. Recently, we identified a presynaptic system for the prevention of synapse loss and neurodegeneration involving the co-chaperone Cysteine String Protein a (CSPa) and a-synuclein. We are currently working on achieving a detailed molecular understanding of this presynaptic pathway. We also aim to further investigate the functions of the ubiquitin-proteosome pathway in synapse maintenance and neuroprotection. Our lab uses mouse genetics in combination with biochemical, biophysical and neurobiological approaches to address these problems.

Figure 1: Transgenic human a-synuclein rescues the growth deficits and lethality CSPa KO mice. A) Breeding strategy. Heterozygous CSPa KO mice (CSP+/-) were mated with heterozygous CSPa KO mice containing an a-synuclein transgene (CSP+/-Syntg). B) Photograph of CSPa KO mice lacking (CSP-/-) or containing the wild type human a-synuclein transgene (CSP-/-Synhtg), and of a wild type littermate (CSP+/+) at 10 weeks. C) Body weights of littermate of male mice (♂) as a function of age. D) Survival of female and male mice as a function of age. For more details: see Chandra et al. (2005) 123, 383-396

Figure 2: Transgenic a-synuclein reverses the neuropathology induced by deletion of CSPa. A. Spinal cord gliosis. Low- and high-resolution micrographs of transverse cervical spinal cord sections from mice with the indicated genotypes stained by immunofluorescence with GFAP antibodies. B. and C. Neuromuscular junction (NMJ) abnormalities. Panel B shows representative images of diaphragm NMJs labeled with fluorescent a-bungarotoxin. Panel C depicts quantitations of the NMJ size. For more details: see Chandra et al. (2005) 123, 383-396.

Recent Publications

S. Chandra, G. Gallardo, R. Fernández-Chacón, O. M. Schlüter, and T. C. Südhof. (2005) a-Synuclein cooperates with CSPa in preventing neurodegeneration. Cell 123, 383-96.

Chandra, S._ and Südhof, T. C. (2008) a-Synuclein, CSPa, SNAREs and
neuroprotection /in vivo/. In: Richard Nass and Serge Przedborski (Eds.),
Parkinson’s disease: Molecular and Therapeutic Insights from Model
Systems. / /Academic Press, New York, pp 295-308.

Chandra, S_. Synucleins. (2008) In: Squire, L., Albright, T., Bloom, F.,
Gage, F. and Spitzer, N. (Eds.), The New Encyclopedia of Neuroscience.
Elsevier

Selected Bibliography

S. Chandra, F. Fornai, H. B. Kwon, U. Yazdani, D. Atasoy, X. Liu, R. E. Hammer, G. Battaglia, D. C. German, P. E. Castillo, and T. C. Südhof. (2004) Double-knockout mice for alpha- and beta-synucleins: effect on synaptic functions. Proc. Natl. Acad. Sci. U S A. 101, 14966-71.

S. Chandra, X. Chen, J. Rizo, R. Jahn, and T. C. Südhof. (2003) A broken a-helix in folded a-synuclein. J. Biol. Chem. 278, 15313-18.

S. Soriano, D. C. Lu, S. Chandra, C. U. Pietrzik, and E. H. Koo. (2001) The amyloidogenic pathway of Amyloid Precursor Protein (APP) is independent of its cleavage by caspases. J. Biol. Chem. 276, 279045-50.

D. C. Lu, S. Rabizadeh, S. Chandra, R. F. Shayya, L. M. Ellerby, X. Ye, G. S. Salvesen, E. H. Koo, and D. E. Bredesen. (2000) A second cytotoxic proteolytic peptide from b- amyloid precursor protein. Nature Med. 6, 397-404.