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- W2128344932 abstract "Oculopharyngeal muscular dystrophy (OPMD) is a late-onset disease caused by (GCN)n triplet expansions in the polyalanine domain coding sequence of the poly(A)-binding protein nuclear 1 (PABPN1). The pathology is characterized by the formation of filamentous intranuclear inclusions (INI) in the nucleus of skeletal muscle fibers. PABPN1 is an ubiquitous polyadenylation factor essential for the lengthening of poly(A) tails on every mRNA. The INIs observed in OPMD are rich in PABPN1, components of ubiquitin–proteasome pathway, molecular chaperones, poly(A)mRNA, and sequester other mRNA-processing factors. Despite a large number of OPMD transgenic and cellular models, the pathologic mechanisms leading the inclusions formation and pathology are still poorly understood. Recent results on other polyalanine expansion diseases suggested that the increased length polyalanine domains could induce a loss-of-function effect by shifting these nuclear proteins to the cytoplasm preventing their normal functions. As the role of the polyalanine domain of PABPN1 in health and disease is still unclear, we decided to study the effect of polyalanine domain length variation on PABPN1 localization and aggregation. In a transfection-based cellular model, we expressed PABPN1 with different sizes of polyalanine domain (0, 10, 13, 17, 30 or 40 alanines). Immunofluorescence, time lapse imagery and toxicity experiments allowed us to follow the localization and aggregation of the proteins in cells. Our results show that long expansions of the polyalanine domain modify aggregation pattern without greatly influencing cell growth and toxicity compared to normal and human disease size mutated isoforms. Furthermore, expression of PABPN1 with no polyalanine domain induces formation of perinuclear inclusions which can sequester other PABPN1 isoforms. These results suggest that the polyalanine domain plays an important role in protein conformation and may have an impact on transport through the nuclear membrane. A better understanding of normal and the modified role of polyalanine domains in proteins may help identify better therapeutic targets for OPMD and other polyalanine domain expansion diseases." @default.
- W2128344932 created "2016-06-24" @default.
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- W2128344932 date "2006-10-01" @default.
- W2128344932 modified "2023-09-25" @default.
- W2128344932 title "G.P.9 02 Long expansion and deletion of the polyalanine domain in PABPN1 lead to a modified aggregation pattern" @default.
- W2128344932 doi "https://doi.org/10.1016/j.nmd.2006.05.216" @default.
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