Publications

Latest publication 01/04/2008

Wild-type PABPN1 is anti-apoptotic and reduces toxicity of the oculopharyngeal m

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset, progressive disease caused by the abnormal expansion of a polyalanine tract-encoding...

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    [title] => Wild-type PABPN1 is anti-apoptotic and reduces toxicity of the oculopharyngeal m
    [paragraph] => Wild-type PABPN1 is anti-apoptotic and reduces toxicity of the oculopharyngeal muscular dystrophy mutation.
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Authors
J. E. Davies, S. Sarkar, D. C. Rubinsztein.

 Lab
Addenbrooke's Hospital, Cambridge Institute for Medical Research, Department of Medical Genetics, Cambridge, UK.
Journal
Human Molecular Genetics
Abstract
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.
BIOSEB Instruments Used
Grip strength test (BIO-GS3)

Keywords/Topics
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An easy way to objectively quantify the muscular strength of mice and rats, and to assess the effect of drugs, toxins, muscular (i.e. myopathy) and neurodegenerative diseases on muscular degeneration. It is widely used in conjunction with the ROTAROD motor coordination test: a normally coordinated rodent will show a decreased latency to fall off the rotating rod if its muscular strength is low. The Grip Strength Test is a must for your research on activity, motor control & coordination, and is particularly well suited for studies on Parkinson's & Huntington's disease.
New features GS4 - 2023: Color display with permanent backlight screen for easier reading, reset by footswitch, Improved battery time, Larger data memory of 500 values, Animal counter, USB port (charging/data transfer)

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