期刊
ACTA NEUROPATHOLOGICA
卷 127, 期 3, 页码 377-389出版社
SPRINGER
DOI: 10.1007/s00401-013-1235-1
关键词
GGGGCC (G(4)C(2)) hexanucleotide repeat expansion; Chromosome 9 open reading frame 72 C9ORF72); Frontotemporal dementia (FTD); Frontotemporal lobar degeneration (FTLD); Amyotrophic lateral sclerosis (ALS); Induced pluripotent stem cells (iPSCs); Drosophila; Zebrafish; Mouse; RNA foci; RNA toxicity; hnRNP; RBP; TDP-43; Sequestration; Repeat associated non-ATG (RAN) translation; Dipeptide-repeat protein (DPR); Repeat-associated neurodegenerative disease
资金
- Strategic Grant Award from The Wellcome Trust and Medical Research Council (MRC) [089701]
- Motor Neuron Disease Association [Hirth/3/400, Hirth/Mar12/6085]
- American ALS Association
- Heaton-Ellis Trust
- MRC [G0900688, MR/L010666/1]
- National Institutes of Health Research Biomedical Research Centre for Mental Health at the South London
- Maudsley National Health Service Foundation Trust
- Psychiatry Research Trust
- European Community [259867]
- Alzheimer's Research UK [Hirth/ARUK/2012]
- Fondation Thierry Latran (DrosALS)
- MRC [G0900635, G1100695, MR/L010666/1, G0600974, G0500289, G0501573, MC_G1000733, G0900688, G0701498] Funding Source: UKRI
- Alzheimers Research UK [ARUK-PhD2012-18] Funding Source: researchfish
- Medical Research Council [MC_G1000733, G0701498, G1100695, MR/L010666/1, G0501573, G0900688, G0600974, G0500289, G0500289B, G0900635] Funding Source: researchfish
- Motor Neurone Disease Association [Hirth/Oct13/868-792] Funding Source: researchfish
- Parkinson's UK [G-0714] Funding Source: researchfish
GGGGCC (G(4)C(2)) hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) has been identified as the most common genetic abnormality in both frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). To investigate the role of C9ORF72-related G(4)C(2) repeat expansion in ALS and FTLD, several animal and cell culture models have been generated that reveal initial insights into the disease pathogenesis of C9 ALS/FTLD. These models include neurons differentiated from patient-derived pluripotent stem cells as well as genetically engineered cells and organisms that knock down C9ORF72 orthologues or express G(4)C(2) repeats. Targeted reduction or knockdown of C9ORF72 homologues in zebrafish and mice so far produced conflicting results which neither rule out, nor confirm reduced expression of C9ORF72 as a pathogenic mechanism in C9 ALS/FTLD. In contrast, studies using patient-derived cells, as well as Drosophila and zebrafish models overexpressing disease-related hexanucleotide expansions, can cause repeat length-dependent formation of RNA foci, which directly and progressively correlate with cellular toxicity. RNA foci formation is accompanied by sequestration of specific RNA-binding proteins (RBPs), including Pur-alpha, hnRNPH and ADARB2, suggesting that G(4)C(2)-mediated sequestration and functional depletion of RBPs are cytotoxic and thus directly contribute to disease. Moreover, these studies provide experimental evidence that repeat-associated non-ATG translation of repeat-containing sense and antisense RNA leads to dipeptide-repeat proteins (DPRs) that can accumulate and aggregate, indicating that accumulation of DPRs may represent another pathogenic pathway underlying C9 ALS/FTLD. These studies in cell and animal models therefore identify RNA toxicity, RBP sequestration and accumulation of DPRs as emerging pathogenic pathways underlying C9 ALS/FTLD.
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