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

TY - JOUR

T1 - Lessons learned from CHMP2B, implications for frontotemporal dementia and amyotrophic lateral sclerosis.

AU - Ugbode, Christopher

AU - West, Ryan John Hatcher

PY - 2020/11/2

Y1 - 2020/11/2

N2 - 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.

AB - 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.

KW - Neurodegeneration

KW - CHMP2B

KW - Therapeutics

KW - Immunity

KW - Proteostasis

KW - FTD

KW - ALS

KW - ESCRT

KW - Motor Neurone Disease

UR - https://www.sciencedirect.com/science/article/pii/S0969996120304198?via%3Dihub

U2 - 10.1016/j.nbd.2020.105144

DO - 10.1016/j.nbd.2020.105144

M3 - Review article

SN - 0969-9961

JO - Neurobiology of disease

JF - Neurobiology of disease

M1 - 105144

ER -