Retrotransposon activation and genomic instability participate to Huntington Disease pathogenesis in a Drosophila melanogaster model

Huntington's disease (HD) is a late-onset, autosomal dominant disorder characterized by progressive motor dysfunction, early death and psychiatric disturbances. The disease is caused by a CAG repeat expansion in the IT15 gene, which elongates a stretch of polyglutamine (polyQ) at the amino-terminus of the HD protein, huntingtin (Htt). Despite the accumulated data on the molecular basis of neurodegeneration, no cure is still available. It is therefore important to keep investigating potential previously unnoticed pathways that may be altered in HD and target of therapeutic treatments. Transposable elements (TEs) are mobile genetic elements that constitute a large fraction of eukaryotic genomes. Retrotransposons represent approximately 40% and 30% of the human and Drosophila genomes. Mounting evidences suggest mammalian L1 elements are normally active during neurogenesis. Interestingly, recent reports show that unregulated activation of TE is associated with neurodegenerative diseases. Our experimental results show that retrotransposon transcripts are up-regulated in HD brain and that their inhibition determines the block of polyQ-dependent neurodegeneration. Moreover, we found a high rate of DNA damage and chromosomal abnormalities in HD brains. Taken together, these data suggest that TE activation and genomic instability represent two important pieces in the complicated puzzle of polyQ-induced neurotoxicity.