ABSTRACT
The haploinsufficiency of C9orf72 is implicated in the most common forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the full spectrum of C9orf72 functions remains to be established. Here, we report that C9orf72 is a mitochondrial inner-membrane-associated protein regulating cellular energy homeostasis via its critical role in the control of oxidative phosphorylation (OXPHOS). The translocation of C9orf72 from the cytosol to the inter-membrane space is mediated by the redox-sensitive AIFM1/CHCHD4 pathway. In mitochondria, C9orf72 specifically stabilizes translocase of inner mitochondrial membrane domain containing 1 (TIMMDC1), a crucial factor for the assembly of OXPHOS complex I. C9orf72 directly recruits the prohibitin complex to inhibit the m-AAA protease-dependent degradation of TIMMDC1. The mitochondrial complex I function is impaired in C9orf72-linked ALS/FTD patient-derived neurons. These results reveal a previously unknown function of C9orf72 in mitochondria and suggest that defective energy metabolism may underlie the pathogenesis of relevant diseases.
Subject(s)
C9orf72 Protein/metabolism , Electron Transport Complex I/metabolism , Energy Metabolism/physiology , ATP-Dependent Proteases/metabolism , ATPases Associated with Diverse Cellular Activities/metabolism , Animals , Apoptosis Inducing Factor/antagonists & inhibitors , Apoptosis Inducing Factor/genetics , Apoptosis Inducing Factor/metabolism , C9orf72 Protein/antagonists & inhibitors , C9orf72 Protein/genetics , Cell Line , Cell Survival , Electron Transport Complex I/chemistry , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Mitochondria/metabolism , Mitochondrial Precursor Protein Import Complex Proteins/antagonists & inhibitors , Mitochondrial Precursor Protein Import Complex Proteins/genetics , Mitochondrial Precursor Protein Import Complex Proteins/metabolism , Neurodegenerative Diseases/metabolism , Neurodegenerative Diseases/pathology , Oxidative Phosphorylation , RNA Interference , RNA, Small Interfering/metabolismABSTRACT
Chromosome 9 open reading frame 72 (C9ORF72) encodes a 54-kDa protein with unknown function that is expressed at high levels in the central nervous system. The C9ORF72 hexanucleotide amplification is one of the most recently discovered repetitive amplification diseases related to neurodegeneration. Its association with amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) spectrum diseases has been fully established, although a causative role for C9ORF72 in Alzheimer's disease (AD) and Parkinson's disease (PD) remains to be established. Therefore, in this article, we will review the evidence for C9ORF72 as a causative factor in neurodegenerative diseases, the underlying mechanisms, and the potential for targeting C9ORF72 as a strategy to alleviate neurodegenerative disease progression.
Subject(s)
C9orf72 Protein/genetics , Neurodegenerative Diseases/genetics , Animals , C9orf72 Protein/antagonists & inhibitors , Disease Models, Animal , Disease Progression , Humans , Mutation , Neurodegenerative Diseases/diagnosis , Neurodegenerative Diseases/drug therapy , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic useABSTRACT
Novel treatments are desperately needed for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In this review article, a survey of emerging small-molecule approaches for ALS and FTD therapies is provided. These approaches include targeting aberrant liquid-liquid phase separation and stress granule assembly, modulation of RNA-protein interactions, inhibition of TDP-43 phosphorylation, inhibition of poly(ADP-ribose) polymerases (PARP), RNA-targeting approaches to reduce RAN translation of dipeptide repeat proteins from repeat expansions of C9ORF72, and novel autophagy activation pathways. This review details the emerging small-molecule tools and leads in these areas, along with a critical perspective on the key challenges facing these opportunities.
