2016 Fiscal Year Final Research Report
Elucidation of dysregulation of exocytosis in sporadic amyotrophic lateral sclerosis
| Project/Area Number |
16K15480
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| Research Category |
Grant-in-Aid for Challenging Exploratory Research
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| Allocation Type | Multi-year Fund |
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| Research Field |
Neurology
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| Research Institution | Nagoya University |
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Principal Investigator |
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| Project Period (FY) |
2016-04-01 – 2017-03-31
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| Keywords | 筋萎縮性側索硬化症 / 運動ニューロン / エクソサイトーシス / 糖尿病 / インスリン |
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| Outline of Final Research Achievements |
TAR DNA-binding protein 43 kDa (TDP-43) encoded by TARDBP gene is an RNA-binding protein, the nuclear depletion of which is the histopathological hallmark of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder affecting both upper and lower motor neurons. Besides motor symptoms, ALS patients often develop non-neuronal signs including glucose intolerance, but underlying pathomechanism is still controversial: impaired insulin secretion and/or insulin resistance. Here we show that ALS subjects have reduced early phase insulin secretion and that nuclear localization TDP-43 is lost in the islets of autopsied pancreas of ALS. Loss of TDP-43 inhibits early phase insulin secretion in both Min6 cells and pancreatic beta cell-specific Tardbp knock-out mice. Nuclear loss of TDP-43 is thus implicated in not only selective loss of motor neurons, but glucose intolerance due to impaired insulin secretion at an early stage of ALS.
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| Free Research Field |
神経内科学
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