期刊
NEUROBIOLOGY OF AGING
卷 35, 期 7, 页码 -出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2014.01.016
关键词
Amyotrophic lateral sclerosis; C9orf72; Frontotemporal dementia; Frontotemporal lobar degeneration; Repeat expansion; Southern blotting
资金
- Oxfordshire Health Services Research Committee and/or Nuffield Oxford Hospitals Fund/Biomedical Research Centre (BRC) Fellowship
- Medical Research Council
- Brains for Dementia Research
- National Institute for Health Research Oxford Biomedical Research Centre based at Oxford University Hospitals National Health Service (NHS) Trust and University of Oxford
- MRC [MR/L022656/1, G1100643, G0700943] Funding Source: UKRI
- Medical Research Council [MR/L010305/1, G1100643, G0700943, MR/L022656/1] Funding Source: researchfish
- Motor Neurone Disease Association [Blake/Mar12/815-791] Funding Source: researchfish
An intronic G4C2 hexanucleotide repeat expansion in C9ORF72 is a major cause of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Several mechanisms including RNA toxicity, repeat-associated non- AUG translation mediated dipeptide protein aggregates, and haploinsufficiency of C9orf72 have been implicated in the molecular pathogenesis of this disorder. The aims of this study were to compare the use of two different Southern blot probes for detection of repeat expansions in an amyotrophic lateral sclerosis and frontotemporal lobar degeneration pathological cohort and to determine the levels of C9orf72 transcript variants and protein isoforms in patients versus control subjects. Our Southern blot studies identified smaller repeat expansions (250-1800 bp) that were only detectable with the flanking probe highlighting the potential for divergent results using different Southern blotting protocols that could complicate genotype-phenotype correlation studies. Further, we characterize a new C9orf72 antibody and show for the first time decreased C9orf72 protein levels in the frontal cortex from patients with a pathological hexanucleotide repeat expansion. These data suggest that a reduction in C9orf72 protein may be a consequence of the disease. (C) 2014 The Authors. Published by Elsevier Inc. All rights reserved.
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