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.

SREBP2 gene therapy targeting striatal astrocytes ameliorates Huntington's disease phenotypes / G. Birolini, G. Verlengia, F. Talpo, C. Maniezzi, L. Zentilin, M. Giacca, P. Conforti, C. Cordiglieri, C. Caccia, V. Leoni, F. Taroni, G. Biella, M. Simonato, E. Cattaneo, M. Valenza. - In: BRAIN. - ISSN 0006-8950. - (2021 May 11). [Epub ahead of print] [10.1093/brain/awab186]

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

G. Birolini
Primo
;
C. Maniezzi;P. Conforti;G. Biella;E. Cattaneo;M. Valenza
Ultimo
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.
Huntington’s disease; SREBP2; astrocytes; cholesterol
Settore BIO/14 - Farmacologia
   European stem cell consortium for neural cell replacement, reprogramming and functional brain repair
   NEUROSTEMCELLREPAIR
   EUROPEAN COMMISSION
   FP7
   602278

   Novel Strategies for Cell-based Neural Reconstruction (NSC-Reconstruct)
   NSC-Reconstruct
   EUROPEAN COMMISSION
   H2020
   874758
11-mag-2021
Article (author)
File in questo prodotto:
File Dimensione Formato  
awab186.pdf

accesso riservato

Tipologia: Publisher's version/PDF
Dimensione 1.19 MB
Formato Adobe PDF
1.19 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/877238
Citazioni
  • ???jsp.display-item.citation.pmc??? 11
  • Scopus 16
  • ???jsp.display-item.citation.isi??? 14
social impact