Cysteine-String Proteins (CSPs)

Cysteine-String Protein Overview

Cysteine string proteins (CSPs), highly conserved proteins associated with synaptic vesicles, are expressed in all synapses and prevents neurodegeneration in humans. CSPs are characterized by a central multiple palmitoylated string of cysteine residues and by an N-terminal J-domain, the latter being a 70-amino acid region of homology shared by bacterial DnaJ. Mammals express three CSP proteins (α, β, γ) that are encoded by the DNAJC5a, b and g genes. CSPα is the major protein expressed in most cells and virtually all neurons. SNAP-25 has been identified as a major client for CSPα.

Fig.1 Structure of human CSPα. (Burgoyne, 2015)

Function

CSP has a characteristic HPD motif in the J-domain. This motif is required to allow them to bind to Hsc70/Hsp70 and act in concert with Hsc70/Hsp70 in the refolding or disaggregation of client proteins. Accumulating evidence suggests that the major mechanism by which CSP prevents neurodegeneration appears to be maintaining the conformation of SNAP-25 and thereby facilitating its entry into the membrane-fusing SNARE (soluble N-ethylmalemide-sensitive factor attachment receptors) complex. SNAP-25 is largely localized to the axonal plasma membrane. As Figure 2 shown, the binding of Hsc70 to SNAP-25 is thought to recruit CSP, thereby altering the conformation of SNAP-25, facilitating its entry onto the SNARE complex that drives membrane fusion.

Besides, a newly surprising finding was that the neurodegeneration and reduced life-span in CSPα KO mice was significantly reversed by overexpressing wild-type or disease-related mutant (A30P) α-synuclein. Conversely, the CSPα KO phenotype was exacerbated by knock-out of α- or β-synuclein.

Fig.2 Chaperoning of SNAP-25 by CSP and Hsc70 at the synapse. (Burgoyne, 2015)

Related Human Diseases

Up to now, at least four independent research groups have revealed an association between mutations in the CSPα-encoding DNAJC5 gene and adult onset neuronal ceroid lipofuscinosis (ANCL). ANCL is the only disease known to be caused by CSP mutations. However, alterations in the activity or expression level of CSP could potentially impact on other neurodegenerative conditions given its neuroprotective function. CSPα can interact with mutant huntingtin containing an expanded polyQ domain but not the wild type protein in vitro. Besides, the expression of CSPα is reduced in degenerating areas of the forebrain in post-mortem samples of Alzheimer's patients.

Research Direction and Therapeutic Implications

Since CSPs are expressed in all synapses and prevents neurodegeneration in humans, drugs that could either increase CSP activity or bypass the requirement for CSP represent potential therapies for human neurodegenerative diseases. In fact, works could be performed to identify compounds that can compensate for the lack of functional CSP in animal models. It might be expected that proteasome inhibition would exacerbate neurodegeneration in CSPα knock-out animal model. In the near future, proteasome inhibitors may have therapeutic applications for CSP-related neurodegenerative diseases.

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Reference

1. Burgoyne, R. D.; Morgan, A. Cysteine string protein (CSP) and its role in preventing neurodegeneration. Seminars in cell & developmental biology. Academic Press, 2015, 40: 153-159.