Huntington's disease (HD) is a late-onset, autosomal dominant disorder characterized by progressive motor dysfunction, cognitive decline and psychiatric disturbances. The most prominent pathological manifestation is a selective loss of medium sized spiny neurons of the striatum. The disease is caused by a CAG repeat expansion in the IT15 gene, which elongates a stretch of polyglutamine at the amino-terminus of the HD protein, Huntingtin (Htt). Despite the accumulation of an impressive amount of 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 replicate through an RNA intermediate and represent approximately 40% and 30% of the human and Drosophila genomes. Mounting evidence suggests mammalian L1 elements are normally active during neurogenesis. Interestingly, recent reports show that unregulated activation of TE is associated with neuropathology.
Our experimental preliminary results obtained in Drosophila melanogaster HD model, suggest that TEs activation may represent an important piece in the complicated puzzle of polyQ-induced neurotoxicity.
Huntington's disease is a genetic disease with devastating consequences. More than 20 years have passed since the identification of the gene harboring the mutation causing HD. Unfortunately, despite the scientific progress in understanding the molecular mechanism of HD pathogenesis, a cure is still not available. It is therefore important to keep investigating potential previously unnoticed pathways that may be altered in HD and target of therapeutic treatments. Our preliminary results obtained in Drosophila provide an original indication that TE activation could be an important element in polyQ induced neurotoxicity. In our preliminary data we show that the neuronal expression of the pathogenic form of human Htt, is able to induce transposon transcripts de-repression in Drosophila larval and adult brains. Importantly, we also find that inhibiting TE mobilization by RT inhibitors lead to block of polyQ-dependent neurodegeneration. If these effects are confirmed, this work can provide new therapeutic strategies to cure or delay this devastating disease considering that retroviral drugs are available and might be repositioned for HD therapy.
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