Accumulation of insoluble forms of FUS protein correlates with toxicity in Drosophila

作者：Miguel Laetitia; Avequin Tracey; Delarue Morgane; Feuillette Sebastien; Frebourg Thierry; Campion Dominique; Lecourtois Magalie^*

来源：Neurobiology of Aging, 2012, 33(5): 1008.e1.

DOI：10.1016/j.neurobiolaging.2011.10.008

• FUS
• Drosophila
• Neurodegeneration
• Frontotemporal lobar degeneration

Recently, the fused in sarcoma/translated in liposarcoma (FUS) protein has been identified as a major constituent of nuclear and/or cytoplasmic ubiquitin-positive inclusions in patients with frontotemporal lobar degeneration or amyotrophic lateral sclerosis. The molecular mechanisms underlying FUS toxicity are currently not understood. To address aspects of FUS pathogenesis in vivo, we have generated new Drosophila transgenic models expressing a full-length wild-type isoform of human FUS protein. We found that when expressed in retinal cells, FUS proteins are mainly recovered as soluble forms, and their overexpression results in a mild eye phenotype, with malformed interommatidial bristles and the appearance of ectopic extensions. On the other hand, when FUS proteins are specifically targeted to adult differentiated neurons, they are mainly recovered as insoluble forms, and their overexpression drastically reduces fly life span. Importantly. FUS neurotoxicity occurs regardless of inclusion formation. Lastly, we showed that molecular chaperones reduce FUS toxicity by modulating protein solubility. Altogether, our data indicate that accumulation of insoluble non-aggregated FUS forms might represent the primary toxic species in human FUS proteinopathies.

• 出版日期2012-5
• 单位河北医科大学