Axonal transport of Hrs is activity-dependent and rate limiting for synaptic vesicle protein degradation

Abstract

Turnover of synaptic vesicle (SV) proteins is vital for the maintenance of healthy, functional synapses in neurons. Our previous work showed that the degradation of SV proteins is mediated by the endosomal sorting complex required for transport (ESCRT) pathway in an activity-dependent manner. Here, we characterize the axonal transport dynamics of ESCRT-0 proteins Hrs and STAM1, the first components of the ESCRT pathway critical for initiating SV protein degradation. Hrs-and STAM1-positive transport vesicles exhibit increased anterograde and bidirectional motility in response to neuronal firing, and frequent colocalization with SV pools. These ESCRT-0 vesicles are a subset of Rab5-positive structures in axons, likely representing pro-degradative early endosomes. Further, we identify kinesin motor protein KIF13A as essential for the activity-dependent transport of ESCRT-0 vesicles as well as the degradation of SV membrane proteins. Together, these data demonstrate a novel KIF13Adependent mechanism for mobilizing axonal transport of ESCRT machinery to facilitate the degradation of SV proteins.Journal 32 (7): 954-69. https://doi.

Keeping synapses in shape: degradation pathways in the healthy and aging brain

“…In Drosophila neurons, endosomal microautophagy mediates the turnover of synaptic proteins harboring a KFERQ recognition motif, including for instance Unc-13/Munc13 and EndophilinA, thereby rejuvenating the protein pool and facilitating synaptic transmission [47]. Given the fact that in the presynapse most organelles and markers for the early stages of the endolysosomal route are present, including MVBs, Rabs and ESCRT components [48][49][50], this route might play an underappreciated but important role in synaptic proteostasis and function and therefore represent an interesting area for future research.…”