Presynaptic protein homeostasis and neuronal function

Proteome integrity is maintained by a coordinated network of molecular chaperones, by protein degradation machineries and by their regulators. Numerous human pathologies are considered as diseases of compromised protein homeostasis (proteostasis), including neurodegeneration. These are characterized by the accumulation of neuronal protein aggregates and by synaptic defects followed by loss of connectivity and cell death. While this suggests that synaptic terminals are particularly sensitive to proteostasis imbalance, our understanding of protein turnover mechanisms and regulation at the synapse remains limited. Recent reports show that different proteolytic pathways act at synapses, including several forms of autophagy. The role of chaperones in controlling the balance between synaptic protein refolding and degradation and how this complex network regulates neuronal function also begins to be unraveled.