期刊
ACTA NEUROPATHOLOGICA
卷 138, 期 1, 页码 49-65出版社
SPRINGER
DOI: 10.1007/s00401-019-01999-w
关键词
C9orf72; ALS; FTD; Nucleocytoplasmic mislocalization; ADAR2; RNA editing; RNA metabolism; iPSC neurons; RNA-seq; Neurodegeneration; Protein accumulation
资金
- National Institute of Neurological Disorders and Stroke, NIH [RO1NS085207]
- Muscular Dystrophy Association
- ALS Association
- Robert Packard Center for ALS Research
- Barrow Neurological Foundation
- NIH [R01NS097850]
- US Department of Defense [W81XWH-15-1-0187]
- Donald E. and Delia B. Baxter Foundation
- Alzheimer's Drug Discovery Foundation
- Association for Frontotemporal Degeneration
- Harrington Discovery Institute
- Tau Consortium
- Pape Adams Foundation
- Frick Foundation for ALS Research
- New York Stem Cell Foundation
- USC Keck School of Medicine Regenerative Medicine Initiative
- USC Broad Innovation Award
- Southern California Clinical and Translational Science Institute
- National Institutes of Health/National Institute of Neurological Disorders and Stroke [R35NS097273, P01NS084974, P01NS099114, R01NS088689]
The hexanucleotide repeat expansion GGGGCC (G(4)C(2))(n) in the C9orf72 gene is the most common genetic abnormality associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent findings suggest that dysfunction of nuclear-cytoplasmic trafficking could affect the transport of RNA binding proteins in C9orf72 ALS/FTD. Here, we provide evidence that the RNA editing enzyme adenosine deaminase acting on RNA 2 (ADAR2) is mislocalized in C9orf72 repeat expansion mediated ALS/FTD. ADAR2 is responsible for adenosine (A) to inosine (I) editing of double-stranded RNA, and its function has been shown to be essential for survival. Here we show the mislocalization of ADAR2 in human induced pluripotent stem cell-derived motor neurons (hiPSC-MNs) from C9orf72 patients, in mice expressing (G(4)C(2))(149), and in C9orf72 ALS/FTD patient postmortem tissue. As a consequence of this mislocalization we observe alterations in RNA editing in our model systems and across multiple brain regions. Analysis of editing at 408,580 known RNA editing sites indicates that there are vast RNA A to I editing aberrations in C9orf72-mediated ALS/FTD. These RNA editing aberrations are found in many cellular pathways, such as the ALS pathway and the crucial EIF2 signaling pathway. Our findings suggest that the mislocalization of ADAR2 in C9orf72 mediated ALS/FTD is responsible for the alteration of RNA processing events that may impact vast cellular functions, including the integrated stress response (ISR) and protein translation.
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