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Insights into novel therapeutic strategies for a nuclear inclusion disease caused by polyalanine expansion

Final Report Summary - POLYALA (Insights into novel therapeutic strategies for a nuclear inclusion disease caused by polyalanine expansion)

A broad range of degenerative diseases is associated with intracellular inclusions formed by toxic, aggregation-prone mutant proteins. Intranuclear inclusions constitute a pathological hallmark of oculopharyngeal muscular dystrophy (OPMD), a rare inherited disease caused by (GCG) repeat expansions in the gene that encodes for nuclear poly(A) binding protein (PABPN1). The mutation results in an extended polyalanine stretch that has been proposed to induce protein aggregation and formation of intranuclear inclusions. The participants in this consortium have previously generated cellular and animal models for OPMD. The POLYALA project aimed to make use of these models to study the molecular mechanisms of OPMD and to develop new strategies for its treatment.

The project has established a competitive European network on OPMD. They have created a communication structure that facilitated the exchange of information, resources and reagents between researchers in the field, and strengthened interactions with patients and patient organisations. Through their website (see online) queries have already been received from OPMD patients and their families, from all over the world.

To maintain and extend the community created by this network and expand its activities beyond the current funding period, partners applied jointly to the e-Rare call for proposals 2009 - European research projects on rare diseases.

In determining whether arginine methylation of PABPN1 is involved in OPMD, preliminary results suggested that an absence of methylation may actually be able to counteract the development of OPMD and is thus in agreement with the biochemical data. Moreover, these results also suggest that a potential sequestration of PRMTs in the PABPN1 aggregates causing undermethylation of other cellular proteins is unlikely to be involved in OPMD. Therefore, methylation experiments were not pursued.

An assay was developed to screen for molecules that could alleviate OPMD-like phenotypes in Drosophila. A molecule was identified that reduces the percentage of abnormal winged flies to 50-60 % when larvae are fed with it. This molecule (called 6AP) is an anti-aggregation molecule previously identified in models of prion disease. The cellular target of 6AP has been identified as being the large ribosomal RNA subunit. The project therefore tried to determine whether the 6AP molecule was active on OPMD through the same cellular pathway. They used the genetic approach to show that the 6AP molecule acts synergistically with a decrease level of ribosomal RNA. The model from these experiments proposes that the ribosomal RNA would be involved in PABPN1 folding leading to aggregation. The 6AP molecule which binds the ribosomal RNA would prevent its function in protein folding and would reduce the aggregation load. These results identify the 6AP as a good suppressor of OPMD in Drosophila. They are of interest because the 6AP appears to have similar molecular effect as other less toxic molecules that should be more useful for future OPMD therapeutic approaches.