2013 Fiscal Year Final Research Report
Study of regionally different pathomechanism in TDP-43-positive inclusions of amyotrophic lateral sclerosis
| Project/Area Number |
23791006
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Neurology
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| Research Institution | Kansai Medical University |
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Principal Investigator |
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| Project Period (FY) |
2011 – 2013
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| Keywords | ALS / TDP-43 / pSmad2/3 / Smurf2 / TGF-beta |
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| Research Abstract |
TDP-43-positive inclusions in lower motor neurones of sporadic Amyotrophic lateral sclerosis (SALS) patients were immunopositive for Smurf2 and pSmad2/3. In contrast, TDP-43-positive inclusions in the extramotor neurones in the brain of SALS patients were noticeably negative for Smurf2 and pSmad2/3. These results demonstrated that the composition of the TDP-43 inclusions is regionally distinct, suggesting different underlying pathogenic processes. We replicated cytoplasmic aggregates of TDP-43 in HEK293T cells by transfecting the cells with a nuclear localization signal deletion mutant of TDP-43 and inhibiting proteasome activity. Overexpression of Smad2 reduced the amount of cytoplasmic aggregates in HEK293T cells, and TGF beta stimulation augmented this reduction effect in a dose-dependent manner. Our results suggest that activation of TGF beta/Smad signaling system may be a potential therapeutic approach to delay the progression of ALS.
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