Synapses need to be actively maintained throughout life to provide for stable neuronal networks and hence normal brain functions. Clinical findings strongly suggest that synapse maintenance is disrupted in common brain disorders, such as mental retardation, schizophrenia, Alzheimer's and Parkinson's disease. Despite its importance, the pathways that control synapse maintenance remain to be defined at a molecular level. Our long term goal is to elucidate the molecular basis of synapse maintenance. CSP?, a presynaptic co-chaperone, is one of the few genes identified to be essential for synapse stability. CSP? binds Heat Shock Cognate 70 (Hsc70) to form a functional chaperone complex on synaptic vesicles. This chaperone complex has been hypothesized to fold presynaptic proteins critical for synaptic stability. The importance of CSP? for human health is underscored by the recent identification of CSP? mutations in adult-onset neuronal ceroid-lipofuscinosis (ANCL), a dominant neurodegenerative disorder with lysosomal pathology. In this proposal, we aim to dissect the CSP? synapse maintenance pathway based on an unbiased proteomic screen that successfully identified protein substrates of the CSP?/Hsc70 chaperone complex. Here, we aim to characterize these CSP?/Hsc70 protein substrates and determine their functions in synaptic stability. Then, we will examine the mechanisms of CSP? dysfunction in ANCL. In particular, we will investigate the role of aberrant protein palmitoylation and CSP?/Hsc70 protein substrate degradation in this disease. These experiments will delineate the first presynaptic maintenance pathway in vertebrates and elucidate the mechanisms of ANCL. Achieving these goals is important for human health, given the wide range of brain disorders that have synaptic loss and dysfunction.
Synapses, sites of communication between neurons, need to be preserved throughout life to allow for normal brain functions and behavior. Aberrant synapse maintenance is linked to mental retardation, schizophrenia, and neurodegenerative diseases. In this study, we will characterize CSP?, a gene that is essential for the maintenance of synapses and examine its dysfunction in disease.
| Vargas, Karina J; Schrod, Nikolas; Davis, Taylor et al. (2017) Synucleins Have Multiple Effects on Presynaptic Architecture. Cell Rep 18:161-173 |
| Taguchi, Yumiko V; Liu, Jun; Ruan, Jiapeng et al. (2017) Glucosylsphingosine Promotes ?-Synuclein Pathology in Mutant GBA-Associated Parkinson's Disease. J Neurosci 37:9617-9631 |
| Gorenberg, Erica L; Chandra, Sreeganga S (2017) The Role of Co-chaperones in Synaptic Proteostasis and Neurodegenerative Disease. Front Neurosci 11:248 |
| Henderson, Michael X; Wirak, Gregory S; Zhang, Yong-Quan et al. (2016) Neuronal ceroid lipofuscinosis with DNAJC5/CSP? mutation has PPT1 pathology and exhibit aberrant protein palmitoylation. Acta Neuropathol 131:621-37 |
| Zhang, Yong-Quan; Chandra, Sreeganga S (2014) Oligomerization of Cysteine String Protein alpha mutants causing adult neuronal ceroid lipofuscinosis. Biochim Biophys Acta 1842:2136-46 |
| Vargas, Karina J; Makani, Sachin; Davis, Taylor et al. (2014) Synucleins regulate the kinetics of synaptic vesicle endocytosis. J Neurosci 34:9364-76 |
| Zhang, Yong-Quan; Henderson, Michael X; Colangelo, Christopher M et al. (2012) Identification of CSP? clients reveals a role in dynamin 1 regulation. Neuron 74:136-50 |
