Titre : | PABPN1 POLYALANINE tract deletion and long expansions modify its aggregation pattern and expression |
contenu dans : | |
Auteurs : | Congrès international de myologie 2008 (International Congress of Myology 2008; 26-30 mai 2008; Marseille, France) ; Klein AF ; Ebihara M ; Alexander C ; Dicaire MJ ; Rouleau GA ; Brais B |
Type de document : | Article |
Année de publication : | 2008 |
Pages : | p. 221 |
Langues: | Anglais |
Résumé : | Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant disease caused by expansions of a (GCN)10/polyalanine tract in the gene coding for the Poly(A) Binding Protein Nuclear 1 (PABPN1). The pathological hallmark of the disease is the presence of filamentous intranuclear inclusions (INI) in the nucleus of skeletal muscle fibers. In cellular and animal models of the disease, INIs can be reproduced by overexpression of PABPN1. Studies on other diseases caused by similar polyalanine expansions have shown that expression of mutated proteins does not cause INIs formation but induces their abnormal accumulation in the cytoplasm. This relocalization appears to be correlated to the length of the polyalanine tract. This study presents the impact on the subcellular localization of PABPN1 produced by large expansions of its polyalanine tract or by its deletion. Large tracts of more than 24 alanines result in the nuclear accumulation of PABPN1 in SFRS2-positive functional speckles and in a significant decline in cell survival. These large expansions do not cause INIs formation nor do they lead to cytoplasmic accumulation. Deletion of the polyalanine tract induces the formation of aggregates that are located at the nuclear membrane, highlighting the possible role of the N-terminal polyalanine tract in PABPN1 nucleo-cytoplasmic transport. We also show that even though five other proteins with polyalanine tracts tend to aggregate when over-expressed they do not co-aggregate with PABPN1 INIs. This study presents the first experimental evidence that there may be a relative loss of function in OPMD by decreasing the availability of PABPN1 through an INI-independent mechanism. |