Abstract
Nutrient utilization and energy metabolism are critical for the maintenance of cellular homeostasis. A mutation in the C9orf72 gene has been linked to the most common forms of neurodegenerative diseases that include amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we have identified an evolutionarily conserved function of C9orf72 in the regulation of the transcription factor EB (TFEB), a master regulator of autophagic and lysosomal genes that is negatively modulated by mTORC1. Loss of the C. elegans orthologue of C9orf72, ALFA-1, causes the nuclear translocation of HLH-30/TFEB, leading to activation of lipolysis and premature lethality during starvation-induced developmental arrest in C. elegans. A similar conserved pathway exists in human cells, in which C9orf72 regulates mTOR and TFEB signaling. C9orf72 interacts with and dynamically regulates the level of Rag GTPases, which are responsible for the recruitment of mTOR and TFEB on the lysosome upon amino acid signals. These results have revealed previously unknown functions of C9orf72 in nutrient sensing and metabolic pathways and suggest that dysregulation of C9orf72 functions could compromise cellular fitness under conditions of nutrient stress.
Highlights
Recognition of a hexanucleotide repeat expansion (HRE) in the C9orf72 gene as the most common cause of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has opened avenues for understanding the molecular mechanisms of a number of neurological diseases [1, 2]
An expansion of repeated nucleotides in the non-coding region of the C9orf72 gene has been linked to the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)
The repeat expansion leads to a reduced expression of the C9orf72 gene and loss of function of the C9orf72 protein may contribute to the pathogenesis
Summary
Recognition of a hexanucleotide repeat expansion (HRE) in the C9orf gene as the most common cause of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has opened avenues for understanding the molecular mechanisms of a number of neurological diseases [1, 2]. In addition to being the most common cause of ALS and FTD, two related neurodegenerative conditions [3], there is genetic evidence to suggest that the C9orf repeat expansion contributes to Alzheimer’s disease [4,5,6,7], Huntington’s disease [8], and other neurological conditions, including multiple system atrophy [9], depressive pseudodementia [10], and bipolar disorder [11]. How the C9orf repeat expansion leads to neurodegeneration remains to be determined, both gain-of-toxicity and lossof-function mechanisms have been proposed. Loss of C9orf hypersensitizes cells to stress [17], and the haploinsufficiency of C9orf leads to neurodegeneration in human motor neurons [18]
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