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. as CSPα substrates including voltage-dependent ion channels signaling proteins and proteins crucial 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. The field is now turning to better appreciate the age interval of CSPα KO mice when the demise of the synapse is likely to begin. While this early windows remains to be fully dissected we know that around 20 proteins have Dock4 altered expression patterns by P28 and that these proteins represent potential main “misfolding events” (Zhang et al. 2012 Activity-dependent degeneration in mice and temperature-sensitive paralysis in are distinguishing features of CSPα null models. In mice synapses that fire frequently such as those associated with photoreceptors and Rosiglitazone GABAergic neurons are lost first (Schmitz et al. 2006 García-Junco-Clemente et al. 2010 Early impairments in motor terminals are characterized by a failure to sustain continuous release and impaired synaptic vesicle recycling (Rozas et al. 2012 In is usually unlikely to be a main cause of neurodegeneration as SNAP25 heterozygous mice with ～50% reduction in SNAP25 levels are phenotypically normal (Washbourne et al. 2002 Sharma et al. 2011 Furthermore the dramatic rescue of neurodegeneration in CSPα KO mice by α-synuclein rescues the association of SNAP25 with other SNAREs but does not ameliorate the decrease in SNAP-25 expression (Sharma et al. 2011 2012 More recently it was shown that treatment of CSPα KO mice with proteasome inhibitors reverses impairment of SNARE-complex assembly and alleviates neurodegeneration (Sharma et al. 2012 CSPα has also been shown to interact with the t-SNARE syntaxin (Nie et al. 1999 Evans et al. 2001 and the Rosiglitazone Ca2+ binding protein synaptotagmin (Evans and Morgan 2002 emphasizing its role in chaperoning the exocytosis machinery. Taken together degeneration in CSPα KO mice is usually halted by interventions that correct SNARE complex function including interventions that influence SNARE complex assembly without elevating SNAP25 levels. A separate line of investigation has revealed that CSPα KO mice also have an Rosiglitazone endocytosis defect resulting in the failure to recycle and maintain the size of the synaptic vesicle pool during continuous activation (Rozas et al. 2012 In fact early on Rosiglitazone (P28) in the course of degeneration the GTPase dynamin 1 which is essential for endocytosis is usually reduced by ～40% in CSPα KO mice (Zhang et al. 2012 CSPα directly interacts with dynamin 1 to promote polymerization a process required in membrane fission (Zhang et al. 2012 however the mechanistic details linking endocytosis and CSPα dysfunction remain to be established. Insights into exocytosis/endocytosis defects will undoubtedly prove to be important in understanding the pathological uncoupling between presynaptic exocytosis and endocytosis. Presynaptic Ion channels: channel proteostasis and multi-Protein Complexes We have shown that large conductance Ca2+-and voltage-activated K+ (BK) channels are ～2.5 fold higher in the brain of CSPα null mice compared with age-matched wild types (Kyle et al. 2013 This increase in expression is usually observed at an early age (i.e. P23-P27) when levels of neuronal Kv1.1 Kv1.2 and Cav2.2 do not switch. Physiologically BK channels are activated by membrane depolarization and/or elevations in intracellular Ca2+ and drive the membrane potential towards K+ equilibrium potential. Under normal conditions BK channels regulate repolarization of the action potential thereby regulating excitability of neurons as well as presynaptic neurotransmitter release. Further ectopic expression of dysfunctional CSPα mutants (i.e. CSPαHPD-AAA CSPαL116Δ CSPαL115R) also elicits elevation of BK channel expression and macroscopic current density (Kyle et al. 2013 Ahrendt et al. 2014 suggesting that the observed increase at least in the beginning displays an elevation of functional rather than mis-folded or aggregated BK channel protein. CSPαHPD-AAA is usually a loss-of-function mutant in which the essential J domain Rosiglitazone required for activation of Hsc70ATPase is usually disrupted but the cysteine string anchor is usually functional. The increase found in the presence of this loss-of-function mutant is usually consistent with the increase in BK channel expression observed in CSPα.