Résumé :
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Communication n° 667 Autosomal dominant oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disease with a worldwide distribution. Intranuclear inclusions (INIs) in skeletal muscle fibers are its pathological hallmark. The dominant OPMD mutations consist in expanded (GCN)8-13 stretches in the poly(A) binding protein nuclear 1 gene (PABPN1). The (GCN) repeat codes for a polyalanine tract at the N-terminus of the PABPN1 protein. The INIs are known to contain PABPN1, molecular chaperones, ubiquitin, proteasomal subunits and poly(A)-mRNAs. We describe an adenoviral model of PABPN1 expression that produces INIs in most cells. Microarray analyses using the Affymetrix human HG-U133A GeneChip show that PABPN1 overexpression induces in our model a reproducible change in the expression of 202 genes. The majority of the 103 upregulated genes encodes nuclear proteins, many of which with RNA or DNA binding activities. Immunofluorescence microscopy studies reveal that all tested nuclear proteins encoded by eight upregulated genes colocalize with PABPN1 in the INIs: CUGBP1, SFRS3, FKBP1A, HMG2, HNRPA1, PRC1, S100P and HSP70. Moreover, we show that CUGBP1, SFRS3 and FKBP1A are also present in OPMD muscle INIs. Our results demonstrate that the INIs are more heterogeneous than previously thought. They may play an active role in the pathophysiology in OPMD by influencing the availability of some nuclear proteins.
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