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

TY - JOUR

T1 - SREBP2 gene therapy targeting striatal astrocytes ameliorates Huntington's disease phenotypes

AU - Birolini, Giulia

AU - Verlengia, Gianluca

AU - Talpo, Francesca

AU - Maniezzi, Claudia

AU - Zentilin, Lorena

AU - Giacca, Mauro

AU - Conforti, Paola

AU - Cordiglieri, Chiara

AU - Caccia, Claudio

AU - Leoni, Valerio

AU - Taroni, Franco

AU - Biella, Gerardo

AU - Simonato, Michele

AU - Cattaneo, Elena

AU - Valenza, Marta

N1 - Funding Information: This work was supported in part by the National Institute of Biomedical Imaging and Bioengineering (NIBIB: R21EB029575 ), the U.S. National Library of Medicine (NLM: R00LM012104 ), the Patient-Centered Outcomes Research Institute (PCORI: ME-2018C1-10963) and the Cancer Prevention Research Institute of Texas (CPRIT: RP160015). Publisher Copyright: © 2021 The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

PY - 2021/10/1

Y1 - 2021/10/1

N2 - 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 SREBP2-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 (hSREBP2). 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 dopamine receptor D2 (Drd2) transcript levels decline, cleared mutant huntingtin aggregates and attenuated behavioural 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.

AB - 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 SREBP2-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 (hSREBP2). 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 dopamine receptor D2 (Drd2) transcript levels decline, cleared mutant huntingtin aggregates and attenuated behavioural 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.

KW - Astrocytes

KW - Cholesterol

KW - Huntington's disease

KW - SREBP2

UR - http://www.scopus.com/inward/record.url?scp=85115900634&partnerID=8YFLogxK

U2 - 10.1093/brain/awab186

DO - 10.1093/brain/awab186

M3 - Article

C2 - 33974044

AN - SCOPUS:85115900634

SN - 0006-8950

VL - 144

SP - 3175

EP - 3190

JO - Brain

JF - Brain

IS - 10

ER -