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Human Molecular Genetics, 2001, Vol. 10, No. 21 2341-2351
© 2001 Oxford University Press

Oligomerization of polyalanine expanded PABPN1 facilitates nuclear protein aggregation that is associated with cell death

Xueping Fan, Patrick Dion, Janet Laganiere, Bernard Brais1 and Guy A. Rouleau+

Center for Research in Neuroscience, McGill University, and the McGill University Health Center, 1650 Cedar Avenue, Montreal, Quebec H3G 1A4, Canada and 1Centre de recherche du CHUM, Hôpital Notre-Dame, Université de Montréal, 1560 Sherbrooke East, Montreal, Quebec H2L 4M1, Canada

Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disorder characterized by progressive eyelid drooping, swallowing difficulties and proximal limb weakness. The autosomal dominant form of this disease is caused by short expansions of a (GCG)6 repeat to (GCG)8–13 in the PABPN1 gene, which results in the expansion of a polyalanine stretch from 10 to 12–17 alanines in the N-terminus of the protein. Mutated PABPN1 (mPABPN1) is able to induce nuclear protein aggregation and form filamentous nuclear inclusions, which are the pathological hallmarks of OPMD. PABPN1, when bound to poly(A) RNA, forms both linear filaments and discrete-sized, compact oligomeric particles in vitro. In the absence of poly(A) RNA, PABPN1 can form oligomers. Here we report that: (i) oligomerization of PABPN1 is mediated by two potential oligomerization domains (ODs); (ii) inactivating oligomerization of mPABPN1 by deletions of 6–8 amino acids in either of the ODs prevents nuclear protein aggregation; (iii) expression of mPABPN1 in COS-7 cells is associated with cell death; and (iv) preventing nuclear protein aggregation by inactivating oligomerization of mPABPN1 significantly reduces cell death. These findings suggest that oligomerization of PABPN1 plays a crucial role in the formation of OPMD nuclear protein aggregation, while the expanded polyalanine stretch is necessary but not sufficient to induce OPMD protein aggregation, and that the nuclear protein aggregation might be toxic and cause cell death. These observations also imply that inactivation of oligomerization of mPABPN1 might be a useful therapeutic strategy for OPMD.

+ To whom correspondence should be addressed at: Room L7-224, Montreal General Hospital, 1650 Cedar Avenue, Montreal, Quebec H3G 1A4, Canada. Tel: +1 514 934 8094; Fax: +1 514 934 8265; Email: mi32@musica.mcgill.ca


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