Progressive myopathy in an inducible mouse model of oculopharyngeal muscular dystrophy

NEUROBIOLOGY OF DISEASE

卷:45

Article

Mankodi, Ami^1,2  Wheeler, Thurman M.²  Shetty, Reena²  Salceies, Kelly M.³  Becher, Mark W.³  Thornton, Charles A.² 

[1] NINDS, Neurogenet Branch, NIH, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA

[2] Univ Rochester, Med Ctr, Dept Neurol, Rochester, NY 14620 USA

[3] Univ New Mexico, Dept Neuropathol, Albuquerque, NM 87131 USA

关键词: Oculopharyngeal muscular dystrophy;    Transgenic mouse model;    PABPN1;    Myopathy;    Cardiomyopathy;    Protein aggregation;    Nuclear inclusion;   

DOI  :  10.1016/j.nbd.2011.09.010

来源: Elsevier

【 摘 要 】

The genetic basis of oculopharyngeal muscular dystrophy (OPMD) is a short expansion of a polyalanine tract (normal allele: 10 alanines, mutant allele: 11-17 alanines) in the nuclear polyadenylate binding protein PABPN1 which is essential for controlling poly(A) tail length in messenger RNA. Mutant PABPN1 forms nuclear inclusions in OPMD muscle. To investigate the pathogenic role of mutant PABPN1 in vivo, we generated a ligand-inducible transgenic mouse model by using the mifepristone-inducible gene expression system. Induction of ubiquitous expression of mutant PABPN1 resulted in skeletal and cardiac myopathy. Histological changes of degenerative myopathy were preceded by nuclear inclusions of insoluble PABPN1. Downregulation of mutant PABPN1 expression attenuated the myopathy and reduced the nuclear burden of insoluble PABPN1. These results support association between mutant PABPN1 accumulation and degenerative myopathy in mice. Resolution of myopathy in mice suggests that the disease process in OPMD patients may be treatable. Published by Elsevier Inc.

【 授权许可】

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