News

2016.04.25 Press Release

Identification of the common pathogenic mechanism of neurodegenerative diseases: Dysfunction of ESCRT, a master regulator of vesicle transport, causes a neuronal cell death.

A research group led by Professor Masashi Aoki and Assistant Professor Takafumi Hasegawa of the Deparment of Neurology in Tohoku University School of Medicine has reported that Dysfunction of ESCRT, a master regulator of vesicle transport, causes a neuronal cell death in the neurodegenerative diseases.

Points
• ESCRT is indispensable for the autophagic clearance of misfolded protein.
• ESCRT dysfunction leads to ER stress-mediated neuronal cell death.
• Necroptosis as well as pan-caspase inhibitors ameliorate the neuronal cell death by ESCRT dysfunction.

Neurodegenerative disorders including Parkinson's disease, amyotrophic lateral sclerosis and Alzheimer's disease represent debilitating and progressive conditions for which no definitive cure is currently available and for which therapeutic interventions remain limited to palliative therapy. Pathologically, these diseases share the common process of protein misfolding and aggregation. These aggregates directly and indirectly attack cellular components, leading to neuronal cell death. Mounting evidence suggests that autophagy machinery plays a key role for the proteolytic degradation of these protein aggregates.

Combining cell culture and animal models, we here demonstrate that (i) ESCRT, a key regulator of vesicle transport, is indispensable for the autophagic clearance of protein aggregates in neuronal cells. Intriguingly, (ii) ESCRT dysfunction causes sustained ER stress, which leads to both caspase-dependent apoptosis and RIPK1/RIPK3-mediated necroptosis (programmed necrosis). Finally, we find that (iii) necroptosis inhibitor as well as pan-caspase inhibitors ameliorate the neurotoxicity in the ESCRT-depleted neuronal cells. Taken together, our findings unveil the molecular pathway that connect ESCRT dysfunction and neuronal cell and pave the way for the novel therapeutic approaches for the incurable, devastating neurodegenerative disorders.

The research result was published in Scientific Reports on April 26, 2016 (GTM). The paper’s title is “ESCRT-0 dysfunction compromises autophagic degradation of protein aggregates and facilitates ER stress-mediated neurodegeneration via apoptotic and necroptotic pathways”

Contact
(About the research)
Professor Hiroaki Shimokawa
Department of Neurology, Tohoku University School of Medicine
TEL: +81-22-717-7189
E-mail: thasegawa*med.tohoku.ac.jp (Replace * with @)

(Public Relations)
Lecturer Hitoshi Inada
Public Relations Office of Tohoku University Graduate School of Medicine
TEL: +81-22-717-7891 FAX: +81-22-717-8187
E-mail: pr-office*med.tohoku.ac.jp (Replace * with @)