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

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-ImaizumiAtsushi Suzuki, Hiroshi Ishiguro, Atsushi Enomoto, Mari Yoshida, Hiroshi Arima, Shin Ichi Muramatsu, Gen Sobue, Masahisa Katsuno

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)3578-3593
Number of pages16
JournalJournal of Clinical Investigation
Volume129
Issue number9
DOIs
Publication statusPublished - 03-09-2019

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Exocytosis
DNA-Binding Proteins
Amyotrophic Lateral Sclerosis
Insulin
Glucose Intolerance
Motor Neurons
L-Type Calcium Channels
RNA-Binding Proteins
Islets of Langerhans
Knockout Mice
Neurodegenerative Diseases
Insulin Resistance
Pancreas
Cultured Cells
Down-Regulation
Cell Line

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Araki, K., Araki, A., Honda, D., Izumoto, T., Hashizume, A., Hijikata, Y., ... Katsuno, M. (2019). TDP-43 regulates early-phase insulin secretion via CaV1.2-mediated exocytosis in islets. Journal of Clinical Investigation, 129(9), 3578-3593. https://doi.org/10.1172/JCI124481
Araki, Kunihiko ; Araki, Amane ; Honda, Daiyu ; Izumoto, Takako ; Hashizume, Atsushi ; Hijikata, Yasuhiro ; Yamada, Shinichiro ; Iguchi, Yohei ; Hara, Akitoshi ; Ikumi, Kazuhiro ; Kawai, Kaori ; Ishigaki, Shinsuke ; Nakamichi, Yoko ; Tsunekawa, Shin ; Seino, Yusuke ; Yamamoto, Akiko ; Takayama, Yasunori ; Hidaka, Shihomi ; Tominaga, Makoto ; Ohara-Imaizumi, Mica ; Suzuki, Atsushi ; Ishiguro, Hiroshi ; Enomoto, Atsushi ; Yoshida, Mari ; Arima, Hiroshi ; Muramatsu, Shin Ichi ; Sobue, Gen ; Katsuno, Masahisa. / TDP-43 regulates early-phase insulin secretion via CaV1.2-mediated exocytosis in islets. In: Journal of Clinical Investigation. 2019 ; Vol. 129, No. 9. pp. 3578-3593.
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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.",
author = "Kunihiko Araki and Amane Araki and Daiyu Honda and Takako Izumoto and Atsushi Hashizume and Yasuhiro Hijikata and Shinichiro Yamada and Yohei Iguchi and Akitoshi Hara and Kazuhiro Ikumi and Kaori Kawai and Shinsuke Ishigaki and Yoko Nakamichi and Shin Tsunekawa and Yusuke Seino and Akiko Yamamoto and Yasunori Takayama and Shihomi Hidaka and Makoto Tominaga and Mica Ohara-Imaizumi and Atsushi Suzuki and Hiroshi Ishiguro and Atsushi Enomoto and Mari Yoshida and Hiroshi Arima and Muramatsu, {Shin Ichi} and Gen Sobue and Masahisa Katsuno",
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Araki, K, Araki, A, Honda, D, Izumoto, T, Hashizume, A, Hijikata, Y, Yamada, S, Iguchi, Y, Hara, A, Ikumi, K, Kawai, K, Ishigaki, S, Nakamichi, Y, Tsunekawa, S, Seino, Y, Yamamoto, A, Takayama, Y, Hidaka, S, Tominaga, M, Ohara-Imaizumi, M, Suzuki, A, Ishiguro, H, Enomoto, A, Yoshida, M, Arima, H, Muramatsu, SI, Sobue, G & Katsuno, M 2019, 'TDP-43 regulates early-phase insulin secretion via CaV1.2-mediated exocytosis in islets', Journal of Clinical Investigation, vol. 129, no. 9, pp. 3578-3593. https://doi.org/10.1172/JCI124481

TDP-43 regulates early-phase insulin secretion via CaV1.2-mediated exocytosis in islets. / Araki, Kunihiko; Araki, Amane; Honda, Daiyu; Izumoto, Takako; Hashizume, Atsushi; Hijikata, Yasuhiro; Yamada, Shinichiro; Iguchi, Yohei; Hara, Akitoshi; Ikumi, Kazuhiro; Kawai, Kaori; Ishigaki, Shinsuke; Nakamichi, Yoko; Tsunekawa, Shin; Seino, Yusuke; Yamamoto, Akiko; Takayama, Yasunori; Hidaka, Shihomi; Tominaga, Makoto; Ohara-Imaizumi, Mica; Suzuki, Atsushi; Ishiguro, Hiroshi; Enomoto, Atsushi; Yoshida, Mari; Arima, Hiroshi; Muramatsu, Shin Ichi; Sobue, Gen; Katsuno, Masahisa.

In: Journal of Clinical Investigation, Vol. 129, No. 9, 03.09.2019, p. 3578-3593.

Research output: Contribution to journalArticle

TY - JOUR

T1 - TDP-43 regulates early-phase insulin secretion via CaV1.2-mediated exocytosis in islets

AU - Araki, Kunihiko

AU - Araki, Amane

AU - Honda, Daiyu

AU - Izumoto, Takako

AU - Hashizume, Atsushi

AU - Hijikata, Yasuhiro

AU - Yamada, Shinichiro

AU - Iguchi, Yohei

AU - Hara, Akitoshi

AU - Ikumi, Kazuhiro

AU - Kawai, Kaori

AU - Ishigaki, Shinsuke

AU - Nakamichi, Yoko

AU - Tsunekawa, Shin

AU - Seino, Yusuke

AU - Yamamoto, Akiko

AU - Takayama, Yasunori

AU - Hidaka, Shihomi

AU - Tominaga, Makoto

AU - Ohara-Imaizumi, Mica

AU - Suzuki, Atsushi

AU - Ishiguro, Hiroshi

AU - Enomoto, Atsushi

AU - Yoshida, Mari

AU - Arima, Hiroshi

AU - Muramatsu, Shin Ichi

AU - Sobue, Gen

AU - Katsuno, Masahisa

PY - 2019/9/3

Y1 - 2019/9/3

N2 - 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.

AB - 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.

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Araki K, Araki A, Honda D, Izumoto T, Hashizume A, Hijikata Y et al. TDP-43 regulates early-phase insulin secretion via CaV1.2-mediated exocytosis in islets. Journal of Clinical Investigation. 2019 Sep 3;129(9):3578-3593. https://doi.org/10.1172/JCI124481