SREBP2 gene therapy targeting striatal astrocytes ameliorates Huntington's disease phenotypes.
Brain
; 144(10): 3175-3190, 2021 11 29.
Article
en En
| MEDLINE
| ID: mdl-33974044
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 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.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Terapia Genética
/
Astrocitos
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Enfermedad de Huntington
/
Técnicas de Transferencia de Gen
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Cuerpo Estriado
/
Proteína 2 de Unión a Elementos Reguladores de Esteroles
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Brain
Año:
2021
Tipo del documento:
Article
País de afiliación:
Italia