Abstract
Autophagy-lysosomal pathway is a cellular protective system to remove aggregated proteins and damaged organelles. Meanwhile, exosome secretion has emerged as a mode to selectively clear the neurotoxic proteins, such as α-synuclein. Mounting evidence suggests that these two cellular processes are coordinated to facilitate the clearance of toxic cellular waste; however the regulators for the transition between these two processes are unclear. Here we show that SCAMP5, a secretory carrier membrane protein significantly induced in the brains of Huntington's disease patients, is quickly and transiently induced by protein stress and autophagic stimulation, and is regulated by the master autophagy transcriptional regulator TFEB. Ironically, SCAMP5 inhibits autophagy flux by blocking the fusion of autophagosomes and lysosomes. Although autophagy is blocked, SCAMP5 does not cause significant protein aggregation in cells. Instead, it promotes the Golgi fragmentation and stimulates the unconventional secretion of the co-localizing α-synuclein via exosome as an exosome component. Therefore, we have identified SCAMP5 as a novel coordinator of autophagy and exosome secretion, which is induced upon protein stress to channel the efficient clearance of toxic proteins via the exosomes rather than autophagy-lysosomal pathway.
Highlights
A common theme for the development of neurodegenerative diseases is the propensity of a number of proteins, such as α-synuclein, Huntingtin (HTT), and Tau, to misfold and form insoluble aggregates [1, 2]
The Secretory carrier membrane protein 5 (SCAMP5) mRNA could be induced by autophagy inducer starvation, Rapamycin, and proteasome inhibitor MG132 (Fig 1A)
As autophagy-lysosomal pathway is activated under all those stress conditions, we examined whether SCAMP5 could be activated by the master lysosomal transcriptional regulator TFEB
Summary
A common theme for the development of neurodegenerative diseases is the propensity of a number of proteins, such as α-synuclein, Huntingtin (HTT), and Tau, to misfold and form insoluble aggregates [1, 2]. These protein aggregates will impair neuronal functions, and eventually cause cell death [3,4,5]. The main cellular pathways to sustain the protein homeostasis are autophagy and ubiquitin proteasome, two intertwining machineries that facilitate the degradation of misfolded proteins, aggregates and even damaged organelles [6]. Mounting evidence has suggested that those aggregation-prone neurotoxic proteins, such as α-synuclein, HTT, Tau, can spread among various brain regions with time. Agents that stimulate protein clearance, such as Rapamycin, have shown neuroprotective activities in various models of neurodegeneration [7, 8].
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