期刊
JOURNAL OF NEUROSCIENCE
卷 27, 期 39, 页码 10530-10534出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3421-07.2007
关键词
caspase; apoptosis; frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTDL-U); amyotrophic lateral sclerosis (ALS); TDP-43; progranulin
资金
- Medical Research Council [G0400356] Funding Source: Medline
- NIA NIH HHS [R01-AG-026251-01] Funding Source: Medline
- MRC [G0400356] Funding Source: UKRI
- Medical Research Council [G0400356] Funding Source: researchfish
TAR DNA binding protein-43 (TDP-43) is the pathologic substrate of neuronal and glial inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTDL-U) and in amyotrophic lateral sclerosis (ALS). Mutations in the progranulin gene (PGRN) have been shown to cause familial FTLD-U. The relationship between progranulin and TDP-43 and their respective roles in neurodegeneration is unknown. We report that progranulin mediates proteolytic cleavage of TDP-43 to generate similar to 35 and similar to 25 kDa species. Suppression of PGRN expression with small interfering RNA leads to caspase-dependent accumulation of TDP-43 fragments that can be inhibited with caspase inhibitor treatment. Cells treated with staurosporine also induced caspase-dependent cleavage and redistribution of TDP-43 from its nuclear localization to cytoplasm. Altered cleavage and redistribution of TDP-43 in cell culture models are similar to findings in FTLD-U and ALS. The results suggest that abnormal metabolism of TDP-43 mediated by progranulin may play a pivotal role in neurodegeneration.
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