Localized synthesis of molecular chaperones sustains neuronal proteostasis

Proteostasis at neuronal projections supports the molecular basis behind long-term information storage and movement control. It is maintained through regulated protein synthesis and degradation and chaperone-assisted protein folding. Using high-resolution fluorescent microscopy, we discovered that neurons localize a subset of chaperone mRNAs to their dendrites and increase this asymmetric localization following proteotoxic stress. The most abundant chaperone mRNA in dendrites encodes for the constitutive heat shock protein 70, HSPA8. Most Hspa8 mRNAs travel in dendrites as single molecules. In the dendrites, Hspa8 mRNAs are locally translated by mono and polyribosomes, and proteotoxic stress further enhances the percentage of mRNAs engaged in translation and their efficiency. We discovered that Fused in Sarcoma (FUS) and heterogenous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1) participate in stress-mediated localization of Hspa8 mRNA in dendrites of mouse and human motor neurons, respectively. As such, FUS knocked down neurons accumulate misfolded proteins in dendrites upon stress exposure. Together, these results reveal a novel mechanism allowing neurons to uphold proteostasis at dendrites and spines upon stress.