A liaison between chaperone-mediated autophagy and exocytotic lysosomes controls the dendritic metastable proteome

Autophagy. 2023 Oct 24. doi: 10.1080/15548627.2023.2274256. Online ahead of print.ABSTRACTThe neuronal metastable proteome includes several aggregation-prone proteins related to neurodegeneration. The complex morphology of neurons with very thin processes and enhanced protein turnover therefore necessitates efficient local machinery to remove excessive protein. In recent work we revealed that chaperone-mediated autophagy (CMA) provides cargo for dendritic exocytic lysosomes, a mechanism that serves in the rapid removal of disease-relevant, supersaturated proteins such as TARDBP/TDP-43 (TAR DNA binding protein) and HTT (huntingtin). We found that lysosomal exocytosis requires docking of the lysosomal protein LAMP2B to the glutamatergic receptor scaffold DLG3/SAP102 and that it is regulated by GRIN/NMDA (N-methyl-D-aspartate)-receptor activity. Thus, the small caliber of dendritic processes might impose a need for local disposal of aggregation-prone proteins like TARDBP and HTT. Moreover, we observed that lysosomal exocytosis might serve in both protein removal and modulation of synaptic processes, and the latter might be an inevitable consequence of the necessity for local disposal of CMA clients in dendrites.PMID:37876225 | DOI:10.1080/15548627.2023.2274256

Source: Autophagy - October 25, 2023 Category: Cytology Authors: Katarzyna M Grochowska Michael R Kreutz Source Type: research