Lessons learned from CHMP2B, implications for frontotemporal dementia and amyotrophic lateral sclerosis

NEUROBIOLOGY OF DISEASE

卷:147

Review

Ugbode, Chris¹  West, Ryan J. H.^2,3 

[1] Univ York, Dept Biol, York YO10 5DD, N Yorkshire, England

[2] Univ Sheffield, Sheffield Inst Translat Neurosci, Sheffield S10 2HQ, S Yorkshire, England

[3] Univ Sheffield, Neurosci Inst, Western Bank, Sheffield S10 2TN, S Yorkshire, England

关键词: Neurodegeneration;    Therapeutics;    Immunity;    Proteostasis;    FTD;    ALS;    ESCRT;    Motor neurone disease;    CHMP2B;   

DOI  :  10.1016/j.nbd.2020.105144

来源: Elsevier

【 摘 要 】

Frontotemporal dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) are two neurodegenerative diseases with clinical, genetic and pathological overlap. As such, they are commonly regarded as a single spectrum disorder, with pure FTD and pure ALS representing distinct ends of a continuum. Dysfunctional endo-lysosomal and autophagic trafficking, leading to impaired proteostasis is common across the FTD-ALS spectrum. These pathways are, in part, mediated by CHMP2B, a protein that coordinates membrane scission events as a core component of the ESCRT machinery. Here we review how ALS and FTD disease causing mutations in CHMP2B have greatly contributed to our understanding of how endosomal-lysosomal and autophagic dysfunction contribute to neurodegeneration, and how in vitro and in vivo models have helped elucidate novel candidates for potential therapeutic intervention with implications across the FTD-ALS spectrum.