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
N1 - Funding Information:
We thank Mika Ito and Naomi Takino (Jichi Medical University) for their help with the production of the AAV vectors. This work was supported by Grants-in-Aid (KAKENHI) from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan (grants 16K09742, 16K15480, 17H04195, and 17K08547 to MK; grants 16K09392 and 16K09393 to HI). This work was partly supported by grants from the Japan Agency of Medical Research and Development (AMED) (grants JP17dm0107105h0002 and JP16kk0205009h0001 to MY). This work was also supported by Grants-in-Aid from the Research Committee of CNS Degenerative Diseases, Research on Policy Planning and Evaluation for Rare and Intractable Diseases, Health, Labor and Welfare Sciences Research Grants, the Ministry of Health, Labor and Welfare, Japan (to MY), a grant from the Naito Foundation (to MK), and a grant from the Hori Sciences & Arts Foundation (to MK).
Publisher Copyright:
© 2019, American Society for Clinical Investigation.
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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U2 - 10.1172/JCI124481
DO - 10.1172/JCI124481
M3 - Article
C2 - 31355778
AN - SCOPUS:85070725025
VL - 129
SP - 3578
EP - 3593
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 9
ER -