ESCRT-0 dysfunction compromises autophagic degradation of protein aggregates and facilitates ER stress-mediated neurodegeneration via apoptotic and necroptotic pathways.
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.
Division of Neurology, Department of Neuroscience and Sensory Organs, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.|Division of Cancer Biology and Therapeutics, Miyagi Cancer Center Research Institute, Natori 981-1293, Japan.
Ryuji
R
Oshima
Division of Neurology, Department of Neuroscience and Sensory Organs, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
Takafumi
T
Hasegawa
Division of Cancer Biology and Therapeutics, Miyagi Cancer Center Research Institute, Natori 981-1293, Japan.
Keiichi
K
Tamai
Division of Neurology, Department of Neuroscience and Sensory Organs, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
Naoto
N
Sugeno
Division of Neurology, Department of Neuroscience and Sensory Organs, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
Shun
S
Yoshida
Division of Neurology, Department of Neuroscience and Sensory Organs, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
Junpei
J
Kobayashi
Division of Neurology, Department of Neuroscience and Sensory Organs, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
Akio
A
Kikuchi
Division of Neurology, Department of Neuroscience and Sensory Organs, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
Toru
T
Baba
Department of Basic Medical Science, Kobe City College of Nursing, Hyogo 651-2103, Japan.
Akira
A
Futatsugi
Division of Pathology, Miyagi Cancer Center Research Institute, Natori 981-1293, Japan.
Ikuro
I
Sato
Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, Natori 981-1293, Japan.
Kennichi
K
Satoh
Department of Neurology, Sendai-Nishitaga Hospital, Sendai 982-8555, Japan.
Atsushi
A
Takeda
Division of Neurology, Department of Neuroscience and Sensory Organs, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
Masashi
M
Aoki
Division of Cancer Biology and Therapeutics, Miyagi Cancer Center Research Institute, Natori 981-1293, Japan.
Nobuyuki
N
Tanaka
D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D002470:Cell Survival; D059865:Endoplasmic Reticulum Stress; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics* / Q000378:metabolism*; D020868:Gene Silencing; D006624:Hippocampus / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D009336:Necrosis; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism*; D016548:Prosencephalon / Q000166:cytology* / Q000378:metabolism; D066329:Protein Aggregates; D015398:Signal Transduction; D057149:Ubiquitinated Proteins / Q000378:metabolism
D056827:Endosomal Sorting Complexes Required for Transport; D010750:Phosphoproteins; D066329:Protein Aggregates; D057149:Ubiquitinated Proteins; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate