期刊
NEUROBIOLOGY OF AGING
卷 36, 期 5, 页码 -出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2015.02.009
关键词
Amyotrophic lateral sclerosis; TDP-43; 3 ' UTR; TARDBP; Fibroblast culture
资金
- ICOMM (Insieme Contro le Malattie del Motoneurone) Association for ALS Research
- Associazione Italiana Sclerosi Laterale Amiotrofica (AISLA)
- Federazione Italiana Gioco Calcio (FIGC)
TAR DNA-binding protein 43 (TDP-43) is a major component of the pathologic inclusions observed in the motor neurons of amyotrophic lateral sclerosis (ALS) patients. We examined TDP-43 expression in primary fibroblasts cultures from 22 ALS patients, including cases with SOD1 (n = 4), TARDBP (n = 4), FUS (n = 2), and C9ORF72 (n = 3) mutations and 9 patients without genetic defect. By using a phosphorylation-independent antibody, 15 patients showed notable alterations of TDP-43 level in the nuclear or cytoplasmic compartments. In particular, a marked accumulation of TDP-43 was observed in the cytoplasm of all cases with C9ORF72 and TARDBP mutations, 1 patient with FUS mutation and 3 patients without genetic defect. Patients with SOD1 mutations revealed a significant reduction of TDP-43 in the nuclei without cytoplasmic mislocalization. These changes were associated with the presence of truncated and phosphorylated TDP-43 species. Our results show that fibroblasts recapitulate some of hallmark TDP-43 abnormalities observed in neuronal cells. The reduction of full-length TDP-43 level in mutant SOD1 cells indicates that at least some SOD1 mutations alter TDP-43 metabolism. (C) 2015 Elsevier Inc. All rights reserved.
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