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Rare Dis. 2014 Jun 12;2:e29515. doi: 10.4161/rdis.29515. eCollection 2014.

FUS-regulated RNA metabolism and DNA damage repair: Implications for amyotrophic lateral sclerosis and frontotemporal dementia pathogenesis.

Author information

1
Manitoba Institute of Cell Biology; Department of Biochemistry & Medical Genetics; Regenerative Medicine Program; University of Manitoba; Winnipeg, MB Canada.
2
Manitoba Institute of Cell Biology; Department of Biochemistry & Medical Genetics; Regenerative Medicine Program; University of Manitoba; Winnipeg, MB Canada ; Faculty of Pharmacy; University of Manitoba; Winnipeg, MB Canada.

Abstract

Cytoplasmic inclusion of RNA binding protein FUS/TLS in neurons and glial cells is a characteristic pathology of a subgroup of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Dysregulation of RNA metabolism caused by FUS cytoplasmic inclusion emerges to be a key event in FUS-associated ALS/FTD pathogenesis. Our recent discovery of a FUS autoregulatory mechanism and its dysregulation in ALS-FUS mutants demonstrated that dysregulated alternative splicing can directly exacerbate the pathological FUS accumulation. We show here that FUS targets RNA for pre-mRNA alternative splicing and for the processing of long intron-containing transcripts, and that these targets are enriched for genes in neurogenesis and gene expression regulation. We also identify that FUS RNA targets are enriched for genes in the DNA damage response pathway. Together, the data support a model in which dysregulated RNA metabolism and DNA damage repair together may render neurons more vulnerable and accelerate neurodegeneration in ALS and FTD.

KEYWORDS:

DNA damage response; FUS/TLS; RNA metabolism; alternative splicing; amyotrophic lateral sclerosis (ALS); frontotemporal dementia (FTD)

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