Brain cholesterol is produced mainly by astrocytes and is important for neuronal function. Its biosynthesis is severely reduced in mouse models of Huntington's disease. One possible mechanism is a diminished nuclear translocation of the transcription factor sterol regulatory element binding protein 2 (SREBP2) and, consequently, reduced activation of SREBP-controlled genes in the cholesterol biosynthesis pathway. Here we evaluated the efficacy of a gene therapy based on the unilateral intra-striatal injection of a recombinant adeno-associated virus 2/5 (AAV2/5) targeting astrocytes specifically and carrying the transcriptionally active N-terminal fragment of human SREBP2. Robust hSREBP2 expression in striatal glial cells in R6/2 Huntington's disease mice activated the transcription of cholesterol biosynthesis pathway genes, restored synaptic transmission, reversed Drd2 transcript levels decline, cleared mutant Huntingtin aggregates and attenuated behavioral deficits. We conclude that glial SREBP2 participates in Huntington's disease brain pathogenesis in vivo and that AAV-based delivery of SREBP2 to astrocytes counteracts key features of the disease.

Birolini, G., Verlengia, G., Talpo, F., Maniezzi, C., Zentilin, L., Giacca, M., et al. (2021). SREBP2 gene therapy targeting striatal astrocytes ameliorates Huntington's disease phenotypes. BRAIN, 144(10), 3175-3190 [10.1093/brain/awab186].

SREBP2 gene therapy targeting striatal astrocytes ameliorates Huntington's disease phenotypes

Talpo, Francesca;Leoni, Valerio;
2021

Abstract

Brain cholesterol is produced mainly by astrocytes and is important for neuronal function. Its biosynthesis is severely reduced in mouse models of Huntington's disease. One possible mechanism is a diminished nuclear translocation of the transcription factor sterol regulatory element binding protein 2 (SREBP2) and, consequently, reduced activation of SREBP-controlled genes in the cholesterol biosynthesis pathway. Here we evaluated the efficacy of a gene therapy based on the unilateral intra-striatal injection of a recombinant adeno-associated virus 2/5 (AAV2/5) targeting astrocytes specifically and carrying the transcriptionally active N-terminal fragment of human SREBP2. Robust hSREBP2 expression in striatal glial cells in R6/2 Huntington's disease mice activated the transcription of cholesterol biosynthesis pathway genes, restored synaptic transmission, reversed Drd2 transcript levels decline, cleared mutant Huntingtin aggregates and attenuated behavioral deficits. We conclude that glial SREBP2 participates in Huntington's disease brain pathogenesis in vivo and that AAV-based delivery of SREBP2 to astrocytes counteracts key features of the disease.
Articolo in rivista - Articolo scientifico
Astrocytes; Cholesterol; Huntington's disease; SREBP2;
English
11-mag-2021
2021
144
10
3175
3190
none
Birolini, G., Verlengia, G., Talpo, F., Maniezzi, C., Zentilin, L., Giacca, M., et al. (2021). SREBP2 gene therapy targeting striatal astrocytes ameliorates Huntington's disease phenotypes. BRAIN, 144(10), 3175-3190 [10.1093/brain/awab186].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/318652
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