Journal
AUTOPHAGY
Volume 17, Issue 11, Pages 3306-3322Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2021.1872189
Keywords
Amyotrophic lateral sclerosis (ALS); autophagy; axonal transport; c9orf72; dipeptide repeat protein (DPR); frontotemporal dementia (FTD); lysosome; smcr8; wdr41
Categories
Funding
- KU Leuven [C1 -C14-17107]
- Opening the Future Fund (KU Leuven)
- Fund for Scientific Research Flanders (FWO-Flanders)
- ALS Liga Belgium
- KU Leuven fund Een Hart voor ALS
- KU Leuven fund Laeversfonds voor ALS Onderzoek
- KU Leuven fund Valery Perrier Race against ALS Fund
- Alzheimer Research Foundation [SAO-FRA 2017/023]
- Flemish Government [VIND 135043]
- Flanders Innovation & Enterpreneurship (IWT grant Project MinE)
- Flanders Innovation & Enterpreneurship (IWT grant iPSCAF)
- Belgian National Lottery
- Latran Foundation
- European Union's Horizon 2020 research and innovation programme [755094]
- European Union's ERA-Netfor Research Programmes on Rare Diseases (INTEGRALS)
- E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders
- H2020 Societal Challenges Programme [755094] Funding Source: H2020 Societal Challenges Programme
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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two distinct classes of neurodegenerative disorders, sharing genetic, cellular, and molecular features. Common features include hexanucleotide repeat expansions in the C9orf72 gene and accumulation of toxic protein aggregates in affected individuals' nervous systems, potentially caused by toxic gain of function from transcribed HRE RNA or DPRs. Furthermore, alterations in protein homeostasis are suggested as a root cause of disease pathogenesis.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two clinically distinct classes of neurodegenerative disorders. Yet, they share a range of genetic, cellular, and molecular features. Hexanucleotide repeat expansions (HREs) in the C9orf72 gene and the accumulation of toxic protein aggregates in the nervous systems of the affected individuals are among such common features. Though the mechanisms by which HREs cause toxicity is not clear, the toxic gain of function due to transcribed HRE RNA or dipeptide repeat proteins (DPRs) produced by repeat-associated non-AUG translation together with a reduction in C9orf72 expression are proposed as the contributing factors for disease pathogenesis in ALS and FTD. In addition, several recent studies point toward alterations in protein homeostasis as one of the root causes of the disease pathogenesis. In this review, we discuss the effects of the C9orf72 HRE in the autophagy-lysosome pathway based on various recent findings. We suggest that dysfunction of the autophagy-lysosome pathway synergizes with toxicity from C9orf72 repeat RNA and DPRs to drive disease pathogenesis.
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