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TDP-43 regulates early-phase insulin secretion via CaV1.2-mediated exocytosis in islets
Kunihiko Araki, … , Gen Sobue, Masahisa Katsuno
Kunihiko Araki, … , Gen Sobue, Masahisa Katsuno
Published July 29, 2019
Citation Information: J Clin Invest. 2019;129(9):3578-3593. https://doi.org/10.1172/JCI124481.
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Research Article Metabolism Neuroscience

TDP-43 regulates early-phase insulin secretion via CaV1.2-mediated exocytosis in islets

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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.

Authors

Kunihiko Araki, Amane Araki, Daiyu Honda, Takako Izumoto, Atsushi Hashizume, Yasuhiro Hijikata, Shinichiro Yamada, Yohei Iguchi, Akitoshi Hara, Kazuhiro Ikumi, Kaori Kawai, Shinsuke Ishigaki, Yoko Nakamichi, Shin Tsunekawa, Yusuke Seino, Akiko Yamamoto, Yasunori Takayama, Shihomi Hidaka, Makoto Tominaga, Mica Ohara-Imaizumi, Atsushi Suzuki, Hiroshi Ishiguro, Atsushi Enomoto, Mari Yoshida, Hiroshi Arima, Shin-ichi Muramatsu, Gen Sobue, Masahisa Katsuno

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Figure 5

TDP-43 regulates the transcription of CaV1.2 calcium channels.

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TDP-43 regulates the transcription of CaV1.2 calcium channels.
(A) Immun...
(A) Immunoprecipitation (IP) of lysates from MIN6 cells overexpressing V5-tagged TDP-43 with rabbit IgG or an anti-V5 antibody (IP-V5), analyzed with immunoblotting with the indicated antibody. (B) RNA-IP of V5 in cultured MIN6 cells. Bound RNA was analyzed with qRT-PCR using the indicated primers. IP efficiency was calculated relative to input. Representative data from triplicate experiments are shown. (C) Schematics of mature mRNA (exon), premature mRNA (intron), and putative promoter are shown over the Cacna1c gene. (D) Each mature mRNA (exon) were analyzed with qRT-PCR using the indicated primers (n = 6 each, unpaired t test). (E) mRNA stability was measured in MIN6 cells (control, T1) treated with 10 mg/mL actinomycin D with qRT-PCR using the indicated Cacna1c and Tuba1a primers (n = 4 each, 2-way ANOVA). The mRNA levels relative to pretreatment were plotted against time after treatment. Residual mRNA levels were compared at 2, 4, 8, and 12 hours after treatment. (F) Each premature mRNA (intron) were analyzed with qRT-PCR using the indicated primers (n = 6 each, unpaired t test). (G) Luciferase reporter assay of the –1542/+257 mouse Cacna1c promoter (n = 10 each, unpaired t test). (H) Human CACNA1C promoter luciferase reporter assay using the LightSwitch promoter reporter GoClone collection (n = 11 each, unpaired t test). Values are mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.005; ****P < 0.001.
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