期刊
JOURNAL OF NEUROSCIENCE
卷 30, 期 2, 页码 639-649出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4988-09.2010
关键词
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资金
- National Institutes of Health (NIH) [2R01 NS039074]
- National Institute of Neurological Disorders and Stroke [2P01 AG022074]
- National Institute on Aging
- J. David Gladstone Institutes
- NIH Extramural Research Facilities Improvement Program Project [C06 RR018928]
- [GM070967/EY014576]
Mutations in the gene encoding TDP-43-the major protein component of neuronal aggregates characteristic of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitin-positive inclusion bodies-have been linked to familial forms of both disorders. Aggregates of TDP-43 in cortical and spinal motorneurons in ALS, or in neurons of the frontal and temporal cortices in FTLD, are closely linked to neuron loss and atrophy in these areas. However, the mechanism by which TDP-43 mutations lead to neurodegeneration is unclear. To investigate the pathogenic role of TDP-43 mutations, we established a model of TDP-43 proteinopathies by expressing fluorescently tagged wild-type and mutant TDP-43 in primary rat cortical neurons. Expression of mutant TDP-43 was toxic to neurons, and mutant-specific toxicity was associated with increased cytoplasmic mislocalization of TDP-43. Inclusion bodies were not necessary for the toxicity and did not affect the risk of cell death. Cellular survival was unaffected by the total amount of exogenous TDP-43 in the nucleus, but the amount of cytoplasmic TDP-43 was a strong and independent predictor of neuronal death. These results suggest that mutant TDP-43 is mislocalized to the cytoplasm, where it exhibits a toxic gain-of-function and induces cell death.
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