Back to Search
Start Over
TDP-43 regulates early-phase insulin secretion via CaV1.2-mediated exocytosis in islets.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2019 Jul 29; Vol. 129 (9), pp. 3578-3593. Date of Electronic Publication: 2019 Jul 29 (Print Publication: 2019). - Publication Year :
- 2019
-
Abstract
- TAR DNA-binding protein 43 kDa (TDP-43), encoded by TARDBP, is an RNA-binding protein, the nuclear depletion of which is the histopathological hallmark of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder affecting both upper and lower motor neurons. Besides motor symptoms, patients with ALS often develop nonneuronal signs including glucose intolerance, but the underlying pathomechanism is still controversial, i.e., whether it is impaired insulin secretion and/or insulin resistance. Here, we showed that ALS subjects reduced early-phase insulin secretion and that the nuclear localization of TDP-43 was lost in the islets of autopsied ALS pancreas. Loss of TDP-43 inhibited exocytosis by downregulating CaV1.2 calcium channels, thereby reducing early-phase insulin secretion in a cultured β cell line (MIN6) and β cell-specific Tardbp knockout mice. Overexpression of CaV1.2 restored early-phase insulin secretion in Tardbp knocked-down MIN6 cells. Our findings suggest that TDP-43 regulates cellular exocytosis mediated by L-type voltage-dependent calcium channels and thus plays an important role in the early phase of insulin secretion by pancreatic islets. Thus, nuclear loss of TDP-43 is implicated in not only the selective loss of motor neurons but also in glucose intolerance due to impaired insulin secretion at an early stage of ALS.
- Subjects :
- Amyotrophic Lateral Sclerosis metabolism
Animals
Blood Glucose metabolism
Case-Control Studies
Cell Nucleus metabolism
Female
Glucose Tolerance Test
Humans
Insulin Resistance
Insulin Secretion
Male
Mice
Mice, Inbred NOD
Mice, Knockout
Motor Skills
Neurons metabolism
Patch-Clamp Techniques
Calcium Channels, L-Type metabolism
DNA-Binding Proteins metabolism
Exocytosis
Insulin metabolism
Islets of Langerhans metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 129
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 31355778
- Full Text :
- https://doi.org/10.1172/JCI124481