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Acta Neuropathol. 2015 Oct;130(4):525-35. doi: 10.1007/s00401-015-1448-6. Epub 2015 Jun 2.

FTD/ALS-associated poly(GR) protein impairs the Notch pathway and is recruited by poly(GA) into cytoplasmic inclusions.

Author information

1
Department of Neurology, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA, 01605, USA.
2
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02216, USA.
3
Department of Neurology, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA, 01605, USA. fen-biao.gao@umassmed.edu.

Abstract

C9ORF72 repeat expansion is the most common genetic mutation in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Abnormal dipeptide repeat proteins (DPRs) generated from repeat-associated non-AUG (RAN) translation of repeat-containing RNAs are thought to be pathogenic; however, the mechanisms are unknown. Here we report that (GR)80 and (PR)80 are toxic in neuronal and non-neuronal cells in Drosophila. In contrast to reported shorter poly(GR) forms, (GR)80 is mostly localized throughout the cytosol without detectable accumulation in the nucleolus, accompanied by suppression of Notch signaling and cell loss in the wing. Some Notch target genes are also downregulated in brains and iPSC-derived cortical neurons of C9ORF72 patients. Increased Notch expression largely suppressed (GR)80-induced cell loss in the wing. When co-expressed in Drosophila, HeLa cells, or human neurons, (GA)80 recruited (GR)80 into cytoplasmic inclusions, partially decreasing the toxicity of (GR)80 and restoring Notch signaling in Drosophila. Thus, different DPRs have opposing roles in cell loss and we identify the Notch pathway as one of the receptor signaling pathways that might be compromised in C9ORF72 FTD/ALS.

KEYWORDS:

ALS; DPR; Drosophila; FTD; Inclusion; Motor neuron; Notch; Poly(GA); Poly(GR); Poly(PR); RAN translation

PMID:
26031661
PMCID:
PMC4575383
DOI:
10.1007/s00401-015-1448-6
[Indexed for MEDLINE]
Free PMC Article

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