ESCRT-0 dysfunction compromises autophagic degradation of protein aggregates and facilitates ER stress-mediated neurodegeneration via apoptotic and necroptotic pathways

Ryuji Oshima, Takafumi Hasegawa, Keiichi Tamai, Naoto Sugeno, Shun Yoshida, Junpei Kobayashi, Akio Kikuchi, Toru Baba, Akira Futatsugi, Ikuro Sato, Kennichi Satoh, Atsushi Takeda, Masashi Aoki, Nobuyuki Tanaka

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)

Abstract

Endosomal sorting required for transport (ESCRT) complexes orchestrate endo-lysosomal sorting of ubiquitinated proteins, multivesicular body formation and autophagic degradation. Defects in the ESCRT pathway have been implicated in many neurodegenerative diseases, but the underlying molecular mechanisms that link them to neurodegeneration remain unknown. In this study, we showed that forebrain-specific ablation of ESCRT-0/Hrs induced marked hippocampal neuronal cell loss accompanied by the accumulation of ubiquitinated proteins, including α-synuclein, TDP-43 and huntingtin as well as the autophagic substrate SQSTM1/p62. Consistent with this, silencing of Hrs in cultured cells not only led to α-synuclein and TDP-43 accumulation in addition to impaired autophagic flux but also suppressed cell viability through the induction of ER stress followed by the activation of JNK and RIPK1, a key regulator of necroptosis. Moreover, necrostatin-1, a specific inhibitor of RIPK1, and pan-caspase inhibitors partially reduced the neurotoxicity in the Hrs-silenced cells. Altogether, these findings suggest that the disruption of ESCRT-0/Hrs in the nervous system compromises autophagic/lysosomal degradation of neurodegenerative disease-related proteins, which thereby triggers ER stress-mediated apoptotic and necroptotic cell death.

Original languageEnglish
Article number24997
JournalScientific reports
Volume6
DOIs
Publication statusPublished - 2016 Apr 26

ASJC Scopus subject areas

  • General

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