Antisense oligonucleotide-mediated disruption of HTT caspase-6 cleavage site ameliorates the phenotype of YAC128 Huntington disease mice - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Neurobiology of Disease Année : 2024

Antisense oligonucleotide-mediated disruption of HTT caspase-6 cleavage site ameliorates the phenotype of YAC128 Huntington disease mice

Elsa C Kuijper
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Maurice Overzier
  • Fonction : Auteur
Ernst Suidgeest
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Oleh Dzyubachyk
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Cécile Maguin
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Jean-Baptiste Pérot
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Yavuz Ariyurek
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Hailiang Mei
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Ronald A.M. Buijsen
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Louise van der Weerd
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Willeke van Roon-Mom
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Résumé

In Huntington disease, cellular toxicity is particularly caused by toxic protein fragments generated from the mutant huntingtin (HTT) protein. By modifying the HTT protein, we aim to reduce proteolytic cleavage and ameliorate the consequences of mutant HTT without lowering total HTT levels. To that end, we use an antisense oligonucleotide (AON) that targets HTT pre-mRNA and induces partial skipping of exon 12, which contains the critical caspase-6 cleavage site. Here, we show that AON-treatment can partially restore the phenotype of YAC128 mice, a mouse model expressing the full-length human HTT gene including 128 CAG-repeats. Wild-type and YAC128 mice were treated intracerebroventricularly with AON12.1, scrambled AON or vehicle starting at 6 months of age and followed up to 12 months of age, when MRI was performed and mice were sacrificed. AON12.1 treatment induced around 40% exon skip and protein modification. The phenotype on body weight and activity, but not rotarod, was restored by AON treatment. Genes differentially expressed in YAC128 striatum changed toward wild-type levels and striatal volume was preserved upon AON12.1 treatment. However, scrambled AON also showed a restorative effect on gene expression and appeared to generally increase brain volume.
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Dates et versions

hal-04400341 , version 1 (17-01-2024)

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Elsa C Kuijper, Maurice Overzier, Ernst Suidgeest, Oleh Dzyubachyk, Cécile Maguin, et al.. Antisense oligonucleotide-mediated disruption of HTT caspase-6 cleavage site ameliorates the phenotype of YAC128 Huntington disease mice. Neurobiology of Disease, 2024, 190, pp.106368. ⟨10.1016/j.nbd.2023.106368⟩. ⟨hal-04400341⟩
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