Spatial coupling of endogenous Tau translation and degradation by neuroproteasomes in dendrites revealed by STARFISH

Cells regulate protein synthesis, folding, and degradation to maintain proteostasis, and disruptions in these processes have been linked to neurodegenerative diseases. In Alzheimer’s disease (AD), the protein Tau mislocalizes from axons to the somatodendritic compartment and aggregates into pathological filaments. Although Tau aggregation is a hallmark of AD, the subcellular dynamics of its synthesis and degradation are not well characterized. Because nascent polypeptides are particularly susceptible to misfolding, local control of Tau synthesis and degradation may be essential to prevent aggregation. Here, we develop STARFISH, a method for visualizing the subcellular site of endogenous mRNA translation in primary neurons and in vivo with single-molecule sensitivity and near-codon resolution, without modifying the nascent polypeptide. Using STARFISH, we show that despite the broad distribution of Mapt mRNA, Tau is translated almost exclusively in neuronal dendrites, revealing an unexpected level of spatial regulation. We further identify that one-third of newly synthesized Tau is co- or peri-translationally degraded in dendrites by a neuronal-specific plasma membrane-associated proteasome, the neuroproteasome. Failure of neuroproteasome-mediated degradation leads to the protein synthesis-dependent accumulation of somatodendritically mislocalized Tau aggregates. These findings define a previously unrecognized proteostasis mechanism that counterbalances the constitutive physiological overproduction of Tau. We speculate that failure of this proteostasis system contributes directly to Tau aggregation in dendrites, defining a new pathomechanism in Alzheimer’s disease.