Synaptic Chaperone Dysfunction as a Convergent Mechanism in Neurodegenerative and Psychiatric Disorders

The heat shock protein (HSP) family comprises six sub-families whose members participate in a wide array of cellular processes. This minireview focuses on three specific heat shock proteins: Hsp90aa and Hsp90ab from the Hsp90 sub-family, Hsc70 (Hspa8) from the Hsp70 sub-family, and the Hsp40 co-chaperone sub-family. In neuronal cells, these HSPs play critical roles in maintaining proper synaptic proteostasis. We have summarized current evidence for how these HSPs act independently and collaboratively to maintain synaptic proteostasis. Importantly, emerging data suggests that synaptic disruptions of Hsp90, Hsc70, or their Hsp40 partners not only contribute to hallmarks of neurodegenerative pathology but also contribute to psychiatric conditions such as depression and post-traumatic stress disorder (PTSD). By integrating findings across these two disease categories, we propose that dysfunctional chaperones at the synapse represent a molecular link between neurodegenerative and neuropsychiatric disorders.