C9orf72 ALS-FTD: recent evidence for dysregulation of the autophagy-lysosome pathway at multiple levels
Open Access
- 26 February 2021
- journal article
- review article
- Published by Taylor & Francis Ltd in Autophagy
- Vol. 17 (11), 3306-3322
- https://doi.org/10.1080/15548627.2021.1872189
Abstract
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. Abbreviation: ALP: autophagy-lysosome pathway; ALS: amyotrophic lateral sclerosis; AMPK: AMP-activated protein kinase; ATG: autophagy-related; ASO: antisense oligonucleotide; C9orf72: C9orf72-SMCR8 complex subunit; DENN: differentially expressed in normal and neoplastic cells; DPR: dipeptide repeat protein; EIF2A/eIF2α: eukaryotic translation initiation factor 2A; ER: endoplasmic reticulum; FTD: frontotemporal dementia; GAP: GTPase-activating protein; GEF: guanine nucleotide exchange factor; HRE: hexanucleotide repeat expansion; iPSC: induced pluripotent stem cell; ISR: integrated stress response; M6PR: mannose-6-phosphate receptor, cation dependent; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MN: motor neuron; MTORC1: mechanistic target of rapamycin kinase complex 1; ND: neurodegenerative disorder; RAN: repeat-associated non-ATG; RB1CC1/FIP200: RB1 inducible coiled-coil 1; SLC66A1/PQLC2: solute carrier family 66 member 1; SMCR8: SMCR8-C9orf72 complex subunit; SQSTM1/p62: sequestosome 1; STX17: syntaxin 17; TARDBP/TDP-43: TAR DNA binding protein; TBK1: TANK binding kinase 1; TFEB: transcription factor EB; ULK1: unc-51 like autophagy activating kinase 1; UPS: ubiquitin-proteasome system; WDR41: WD repeat domain 41.Keywords
Funding Information
- ALS Liga Belgium, the KU Leuven funds “Een Hart voor ALS”, “Laeversfonds voor ALS Onderzoek” and the “Valéry Perrier Race against ALS Fund”
- Fonds Wetenschappelijk Onderzoek
- KU Leuven (C1 - C14-17-107)
- Stichting Alzheimer Onderzoek - Fondation de Recherche Alzheimer (SAO-FRA 2017/023)
- Flanders Impulse Program on Networks for Dementia Research (VIND 135043)
- ERA-Net for Research Programmes on Rare Diseases
- ALS liga Belgium
- Poverty and Race Research Action Council
This publication has 200 references indexed in Scilit:
- Reduced C9orf72 gene expression in c9FTD/ALS is caused by histone trimethylation, an epigenetic event detectable in bloodActa Neuropathologica, 2013
- Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neuronsActa Neuropathologica, 2013
- Autophagy receptors link myosin VI to autophagosomes to mediate Tom1-dependent autophagosome maturation and fusion with the lysosomeNature, 2012
- The Seeds of Neurodegeneration: Prion-like Spreading in ALSCell, 2011
- Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALSNeuron, 2011
- A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTDNeuron, 2011
- Autophagy fights disease through cellular self-digestionNature, 2008
- Autophagy in the Pathogenesis of DiseaseCell, 2008
- Suppression of basal autophagy in neural cells causes neurodegenerative disease in miceNature, 2006
- Loss of autophagy in the central nervous system causes neurodegeneration in miceNature, 2006