Huntington's disease (HD) is an autosomal dominant disorder with progressive motor dysfunction and cognitive decline. The disease is caused by a CAG repeat expansion in the IT15 gene, which elongates a polyglutamine stretch of the HD protein, Huntingtin. No therapeutic treatments are available, and new pharmacological targets are needed. Retrotransposons are transposable elements (TEs) that represent 40% and 30% of the human and Drosophila genomes and replicate through an RNA intermediate. Mounting evidence suggests that mammalian TEs are active during neurogenesis and may be involved in diseases of the nervous system. Here we show that TE expression and mobilization are increased in a Drosophila melanogaster HD model. By inhibiting TE mobilization with Reverse Transcriptase inhibitors, polyQ-dependent eye neurodegeneration and genome instability in larval brains are rescued and fly lifespan is increased. These results suggest that TE activation may be involved in polyQ-induced neurotoxicity and a potential pharmacological target.

Transposable element activation promotes neurodegeneration in a Drosophila model of Huntington's disease / Casale, A. M.; Liguori, F.; Ansaloni, F.; Cappucci, U.; Finaurini, S.; Spirito, G.; Persichetti, F.; Sanges, R.; Gustincich, S.; Piacentini, L.. - In: ISCIENCE. - ISSN 2589-0042. - 25:1(2022), pp. 1-25. [10.1016/j.isci.2021.103702]

Transposable element activation promotes neurodegeneration in a Drosophila model of Huntington's disease

Ansaloni F.
Membro del Collaboration group
;
Finaurini S.
Membro del Collaboration group
;
Spirito G.
Membro del Collaboration group
;
Sanges R.
Membro del Collaboration group
;
Gustincich S.
Membro del Collaboration group
;
2022-01-01

Abstract

Huntington's disease (HD) is an autosomal dominant disorder with progressive motor dysfunction and cognitive decline. The disease is caused by a CAG repeat expansion in the IT15 gene, which elongates a polyglutamine stretch of the HD protein, Huntingtin. No therapeutic treatments are available, and new pharmacological targets are needed. Retrotransposons are transposable elements (TEs) that represent 40% and 30% of the human and Drosophila genomes and replicate through an RNA intermediate. Mounting evidence suggests that mammalian TEs are active during neurogenesis and may be involved in diseases of the nervous system. Here we show that TE expression and mobilization are increased in a Drosophila melanogaster HD model. By inhibiting TE mobilization with Reverse Transcriptase inhibitors, polyQ-dependent eye neurodegeneration and genome instability in larval brains are rescued and fly lifespan is increased. These results suggest that TE activation may be involved in polyQ-induced neurotoxicity and a potential pharmacological target.
25
1
1
25
103702
10.1016/j.isci.2021.103702
https://www.biorxiv.org/content/10.1101/2020.11.19.389718v3.full.pdf
Casale, A. M.; Liguori, F.; Ansaloni, F.; Cappucci, U.; Finaurini, S.; Spirito, G.; Persichetti, F.; Sanges, R.; Gustincich, S.; Piacentini, L.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11767/127677
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