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Human Molecular Genetics Advance Access originally published online on January 4, 2008
Human Molecular Genetics 2008 17(8):1097-1108; doi:10.1093/hmg/ddm382
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Wild-type PABPN1 is anti-apoptotic and reduces toxicity of the oculopharyngeal muscular dystrophy mutation

Janet E. Davies, Sovan Sarkar and David C. Rubinsztein*

Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK

* To whom correspondence should be addressed. Tel: +44 1223762608; Fax: +44 1223331206; Email: dcr1000{at}hermes.cam.ac.uk

Received October 17, 2007; Revised December 7, 2007; Accepted December 26, 2007

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset, progressive disease caused by the abnormal expansion of a polyalanine tract-encoding (GCG)n trinucleotide repeat in the poly-(A) binding protein nuclear 1 (PABPN1) gene. OPMD is generally inherited as an autosomal dominant disorder and the polyalanine expansion mutation is thought to confer a toxic gain-of-function on mutant PABPN1 which forms aggregates within skeletal myocyte nuclei. Here we describe a novel beneficial function of wild-type PABPN1. Wild-type PABPN1 over-expression can reduce mutant PABPN1 toxicity in both cell and mouse models of OPMD. In addition, wild-type PABPN1 provides some protection to cells against pro-apoptotic insults distinct from the OPMD mutation such as staurosporine treatment and Bax expression. Conversely, PABPN1 knockdown (which itself is not toxic) makes cells more susceptible to apoptotic stimuli. The protective effect of wild-type PABPN1 is mediated by its regulation of X-linked inhibitor of apoptosis (XIAP) protein translation. This normal activity of PABPN1 is partially lost for mutant PABPN1; elevated levels of XIAP are seen in mice expressing a wild-type but not a mutant PABPN1 transgene. This raises the possibility that a compromise of the anti-apoptotic function of PABPN1 might contribute to the disease mechanism of OPMD.


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