Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

RNAi-based GluN3A silencing prevents and reverses disease phenotypes induced by mutant huntingtin

Marco, Sonia, Murillo Bartolome, Alvaro ORCID: and Pérez-Otaño, Isabel 2018. RNAi-based GluN3A silencing prevents and reverses disease phenotypes induced by mutant huntingtin. Molecular Therapy 26 (8) , pp. 1965-1972. 10.1016/j.ymthe.2018.05.013

Full text not available from this repository.


Huntington’s disease (HD) is a dominantly inherited neurodegenerative disease caused by expansion of a polyglutamine tract in the huntingtin protein. HD symptoms include severe motor, cognitive, and psychiatric impairments that result from dysfunction and later degeneration of medium-sized spiny neurons (MSNs) in the striatum. A key early pathogenic mechanism is dysregulated synaptic transmission due to enhanced surface expression of juvenile NMDA-type glutamate receptors containing GluN3A subunits, which trigger the aberrant pruning of synapses formed by cortical afferents onto MSNs. Here, we tested the therapeutic potential of silencing GluN3A expression in YAC128 mice, a well-established HD model. Recombinant adeno-associated viruses encoding a short-hairpin RNA against GluN3A (rAAV-shGluN3A) were generated, and the ability of different serotypes to transduce MSNs was compared. A single injection of rAAV9-shGluN3A into the striatum of 1-month-old mice drove potent (>90%) and long-lasting reductions of GluN3A expression in MSNs, prevented dendritic spine loss and improved motor performance in YAC128 mice. Later delivery, when spine pathology is already apparent, was also effective. Our data provide proof-of-concept for GluN3A silencing as a beneficial strategy to prevent or reverse corticostriatal disconnectivity and motor impairment in HD and support the use of RNAi-based or small-molecule approaches for harnessing this therapeutic potential.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Elsevier (Cell Press)
ISSN: 1525-0016
Date of First Compliant Deposit: 21 December 2020
Date of Acceptance: 12 May 2018
Last Modified: 09 Nov 2022 09:49

Citation Data

Cited 11 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item