CSPα—chaperoning presynaptic proteins

Abstract

Synaptic transmission relies on precisely regulated and exceedingly fast protein-protein interactions that involve voltage-gated channels, the exocytosis/endocytosis machinery as well as signaling pathways. Although we have gained an ever more detailed picture of synaptic architecture much remains to be learned about how synapses are maintained. Synaptic chaperones are “folding catalysts” that preserve proteostasis by regulating protein conformation (and therefore protein function) and prevent unwanted protein-protein interactions. Failure to maintain synapses is an early hallmark of several degenerative diseases. Cysteine string protein (CSPα) is a presynaptic vesicle protein and molecular chaperone that has a central role in preventing synaptic loss and neurodegeneration. Over the past few years, a number of different “client proteins” have been implicated as CSPα substrates including voltage-dependent ion channels, signaling proteins and proteins critical to the synaptic vesicle cycle. Here we review the ion channels and synaptic protein complexes under the influence of CSPα and discuss gaps in our current knowledge.

Lu TH y: a double‐readout bioluminescence‐based two‐hybrid technology for quantitative mapping of protein–protein interactions in mammalian cells

“…In addition, we created a plasmid for the expression of PA‐mCit‐tagged CSPα, a molecular chaperone in the synapse (Sharma et al , ). CSPα maintains protein homeostasis in the presynapse and likely associates with multiple proteins that play a role in synaptic transmission (Zhang et al , ; Donnelier & Braun, ). To this day, however, only a few direct binding partners such as SNAP25 or dynamin‐1 have been identified (Sharma et al , ; Zhang et al , ), suggesting that additional PPIs can be found by targeted interaction screening.…”

“…For validation and also upscaling, we performed targeted PPI screens with libraries of > 120 synaptic or non‐synaptic control proteins against the presynaptic chaperone CSPα (Donnelier & Braun, ). Identification of 42 synaptic proteins, with > 90% not yet described as CSPα partners, indicates that only few of the CSPα‐interacting proteins in the presynapse are currently known and confirms the protein's functional role in various synaptic processes (Südhof & Rizo, ).…”

The zebrafish pinball wizard gene encodes WRB, a tail‐anchored‐protein receptor essential for inner‐ear hair cells and retinal photoreceptors

“…Rab3 and CSP/Dnajc5 are the major protein components in a purified preparation of brain synaptic vesicles (Takamori et al . ; Donnelier & Braun ) and are located in the ribbon synapse (Uthaiah & Hudspeth, ). Rab3 attaches to synaptic vesicles through the C‐terminal geranyl‐geranyl moiety; cysteine‐string protein (CSP/Dnajc5) binds to synaptic vesicles through the palmitoyl residues of the cysteine strings near its centre and is a chaperone protein involved in rescue of unfolded synaptic proteins.…”

The Notch ligand E3 ligase, Mind Bomb1, regulates glutamate receptor localization in Drosophila

“…Both cysteine string protein (CSP) and Fasciclin II (FasII) levels, however, were significantly affected in mib1 3 / mib1 EY09780 mutants. CSP, a vesicle-associated protein important for evoked neurotransmitter release (Bronk et al , 2005) and presynaptic protein folding (Donnelier & Braun, 2014), was significantly reduced at mib1 3 / mib1 EY09780 mutant NMJs (Fig. 7B).…”