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

Chris Ugbode,Ryan J.H West

doi:10.1016/j.nbd.2020.105144

Abstract

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.

Highlights

Frontotemporal Dementia (FTD) is a common cause of early-onset dementia with a typical age of onset under 65 years
FTD is frequently used as an umbrella term referring to a heterogeneous group of neurodegenerative disorders associated with Frontotemporal lobar degeneration (FTLD), a progressive atrophy of the frontal and temporal cortices
FTD and Amyotrophic Lateral Sclerosis (ALS) show significant genetic, neuropathological and clinical overlap with approximately 14% of FTD patients displaying concomitant motor neurone disease (Phukan et al, 2012). This has led to the general consensus that FTD and ALS represent a continuum of a single spectrum disorder

Summary

Introduction

Frontotemporal Dementia (FTD) is a common cause of early-onset dementia with a typical age of onset under 65 years. Neurons expressing wild type CHMP2B rarely showed GFP positive puncta, indicating normal autophagosome-lysosome fusion leading to quenching of the pH-sensitive GFP tag These observations were recapitulated in vivo using Drosophila, identifying autophagosome accumulation and dysfunctional phagosomal-lysosomal fusion as a conserved feature of CHMP2BIntron[5] pathology (West et al, 2020). In addition to supporting previous observations that CHMP2BIntron[5] mediated perturbations to endosomal-lysosomal trafficking significantly impairs normal receptor homeostasis, these findings contribute to an increasing number of studies implicating altered Notch signalling in FTD-ALS neurodegeneration (Gomez-Pinedo et al, 2019; Liu et al, 2020; Nonneman et al, 2018; Wang et al, 2015; Yang et al, 2015). Journal Pre-proof of FTD and ALS, the fundamental role of CHMP2B and the ESCRT machinery in the regulation of neuronal proteostasis, endosomal-lysosomal and autophagic trafficking events, means that models of CHMP2B have contributed to our understanding of the mechanisms driving neurodegeneration across the FTD-ALS spectrum more broadly. This is evidenced by a number of clinical trials monitoring UDCA and it’s taurine conjugate form, TUDCA in ALS (Trial Number NCT00877604) and Parkinson’s Disease (Trial Number NCT03840005) patients

Conclusion

Findings

Accumulation of Enlarged Autophagosomes