Mitochondrial localization of PABPN1 in oculopharyngeal muscular dystrophy

Tsukasa Doki, Satoshi Yamashita, Fan Yan Wei, Kentaro Hara, Takahiro Yamamoto, Ziwei Zhang, Xiao Zhang, Nozomu Tawara, Hirotake Hino, Eiichiro Uyama, Takashi Kurashige, Hirofumi Maruyama, Kazuhito Tomizawa, Yukio Ando

Research output: Contribution to journalArticle

Abstract

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset disorder characterized by ptosis, dysphagia, and weakness of proximal limbs. OPMD is caused by the expansion of polyalanine in poly(A)-binding protein, nuclear 1 (PABPN1). Although mitochondrial abnormality has been proposed as the possible etiology, the molecular pathogenesis is still poorly understood. The aim of the study was to specify the mechanism by which expanded PABPN1 causes mitochondrial dysfunction in OPMD. We evaluated whether transgenic mouse model of OPMD, by expressing expanded PABPN1, indeed causes mitochondrial abnormality associated with muscle degeneration. We also investigated the mechanism by which expanded PABPN1 would cause mitochondrial dysfunction in the mouse and cell models of OPMD. Mitochondrial localization of PABPN1 was observed in the muscle fibers of patients with OPMD. Moreover, abnormal accumulation of PABPN1 on the inner membrane of mitochondria and reduced expression of OXPHOS complexes were detected in the muscle fibers of the transgenic mice expressing expanded human PABPN1 with a 13-alanine stretch. In cells expressing PABPN1 with a 10-alanine or 18-alanine stretch, both types of PABPN1 accumulated in the mitochondria and interacted with TIM23 mitochondrial protein import complex, but PABPN1 with 18-alanine stretch decreased the cell viability and aggresome formation. We proposed that the abnormal accumulation of expanded PABPN1 in mitochondria may be associated with mitochondrial abnormality in OPMD.

Original languageEnglish
JournalLaboratory Investigation
DOIs
Publication statusPublished - Jan 1 2019
Externally publishedYes

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Poly(A)-Binding Protein II
Oculopharyngeal Muscular Dystrophy
Alanine
Mitochondria
Muscles
Transgenic Mice
Mitochondrial Proteins
Deglutition Disorders

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

Cite this

Doki, T., Yamashita, S., Wei, F. Y., Hara, K., Yamamoto, T., Zhang, Z., ... Ando, Y. (2019). Mitochondrial localization of PABPN1 in oculopharyngeal muscular dystrophy. Laboratory Investigation. https://doi.org/10.1038/s41374-019-0243-8

Mitochondrial localization of PABPN1 in oculopharyngeal muscular dystrophy. / Doki, Tsukasa; Yamashita, Satoshi; Wei, Fan Yan; Hara, Kentaro; Yamamoto, Takahiro; Zhang, Ziwei; Zhang, Xiao; Tawara, Nozomu; Hino, Hirotake; Uyama, Eiichiro; Kurashige, Takashi; Maruyama, Hirofumi; Tomizawa, Kazuhito; Ando, Yukio.

In: Laboratory Investigation, 01.01.2019.

Research output: Contribution to journalArticle

Doki, T, Yamashita, S, Wei, FY, Hara, K, Yamamoto, T, Zhang, Z, Zhang, X, Tawara, N, Hino, H, Uyama, E, Kurashige, T, Maruyama, H, Tomizawa, K & Ando, Y 2019, 'Mitochondrial localization of PABPN1 in oculopharyngeal muscular dystrophy', Laboratory Investigation. https://doi.org/10.1038/s41374-019-0243-8
Doki, Tsukasa ; Yamashita, Satoshi ; Wei, Fan Yan ; Hara, Kentaro ; Yamamoto, Takahiro ; Zhang, Ziwei ; Zhang, Xiao ; Tawara, Nozomu ; Hino, Hirotake ; Uyama, Eiichiro ; Kurashige, Takashi ; Maruyama, Hirofumi ; Tomizawa, Kazuhito ; Ando, Yukio. / Mitochondrial localization of PABPN1 in oculopharyngeal muscular dystrophy. In: Laboratory Investigation. 2019.
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