Abstract
Disrupted nucleocytoplasmic transport (NCT) has been implicated in neurodegenerative disease pathogenesis; however, the mechanisms by which disrupted NCT causes neurodegeneration remain unclear. In a Drosophila screen, we identified ref(2)P/p62, a key regulator of autophagy, as a potent suppressor of neurodegeneration caused by the GGGGCC hexanucleotide repeat expansion (G4C2 HRE) in C9orf72 that causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We found that p62 is increased and forms ubiquitinated aggregates due to decreased autophagic cargo degradation. Immunofluorescence and electron microscopy of Drosophila tissues demonstrate an accumulation of lysosome-like organelles that precedes neurodegeneration. These phenotypes are partially caused by cytoplasmic mislocalization of Mitf/TFEB, a key transcriptional regulator of autophagolysosomal function. Additionally, TFEB is mislocalized and downregulated in human cells expressing GGGGCC repeats and in C9-ALS patient motor cortex. Our data suggest that the C9orf72-HRE impairs Mitf/TFEB nuclear import, thereby disrupting autophagy and exacerbating proteostasis defects in C9-ALS/FTD.
Highlights
A GGGGCC (G4C2) hexanucleotide repeat expansion (HRE) in chromosome nine open reading frame 72 (C9orf72) is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), accounting for up to 40% of cases of familial ALS (DeJesusHernandez et al, 2011; ITALSGEN Consortium et al, 2011)
Cell Biology Neuroscience lysosome function, though neurodegeneration is not observed in C9orf72 knockout mice (Liu et al, 2016; Shi et al, 2018; Webster et al, 2016), suggesting that C9-ALS/FTD is primarily caused by toxicity of the HRE
We find that autophagolysosomal defects are caused by loss of nuclear localization of the transcription factor Mitf, which regulates transcription of genes involved in autophagolysosome biogenesis (Boucheet al., 2016; Palmieri et al, 2011; Sardiello et al, 2009; Zhang et al, 2015b)
Summary
A GGGGCC (G4C2) hexanucleotide repeat expansion (HRE) in chromosome nine open reading frame 72 (C9orf72) is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), accounting for up to 40% of cases of familial ALS (DeJesusHernandez et al, 2011; ITALSGEN Consortium et al, 2011). Expression of G4C2 repeats causes neurotoxicity in Drosophila and cell culture models of C9-ALS (Goodman et al, 2019a; Kramer et al, 2016; Tran et al, 2015). This toxicity has been proposed to occur through either G4C2 repeat RNA-mediated sequestration of RNA-binding proteins or translation of the G4C2 repeats into dipeptide-repeat proteins (DPRs) through non-canonical repeat-associated non-AUG (RAN) translation (Donnelly et al, 2013; Goodman et al, 2019a; Mori et al, 2013; Tran et al, 2015)
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