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 language | English |
|---|---|
| Journal | Laboratory Investigation |
| DOIs | |
| Publication status | Published - Jan 1 2019 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Pathology and Forensic Medicine
- Molecular Biology
- Cell Biology
Cite this
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 journal › Article
}
TY - JOUR
T1 - Mitochondrial localization of PABPN1 in oculopharyngeal muscular dystrophy
AU - Doki, Tsukasa
AU - Yamashita, Satoshi
AU - Wei, Fan Yan
AU - Hara, Kentaro
AU - Yamamoto, Takahiro
AU - Zhang, Ziwei
AU - Zhang, Xiao
AU - Tawara, Nozomu
AU - Hino, Hirotake
AU - Uyama, Eiichiro
AU - Kurashige, Takashi
AU - Maruyama, Hirofumi
AU - Tomizawa, Kazuhito
AU - Ando, Yukio
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85063304146&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85063304146&partnerID=8YFLogxK
U2 - 10.1038/s41374-019-0243-8
DO - 10.1038/s41374-019-0243-8
M3 - Article
AN - SCOPUS:85063304146
JO - Laboratory Investigation
JF - Laboratory Investigation
SN - 0023-6837
ER -