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- W4377029358 abstract "<b>Abstract ID 18502</b> <b>Poster Board 202</b> Huntington’s disease (HD) is an incurable, fatal neurodegenerative disease caused by an abnormal expansion in the huntingtin protein (mHTT) leading to progressive motor and cognitive impairments in patients. HD pathophysiology involves evident dysfunctions in glutamatergic neurotransmission leading to severe striatal neurodegeneration. In this context, vesicular glutamate transporter subtype-3 (VGLUT3) represents a promising therapeutic target, being a modulator of glutamate release from selected glutamatergic and non-glutamatergic neurons that are affected by HD. Nevertheless, current evidence on the role of VGLUT3 in HD pathophysiology remains largely unknown. Here, we employed two genetically modified mice in which the <i>Slc17a8</i> gene is deleted in both male and female wild-type (VGLUT3<sup>–/–</sup>) and zQ175 knock-in mouse model of HD (zQ175:VGLUT3<sup>–/–</sup>). Longitudinal assessment of motor and cognitive function reveals that VGLUT3 deletion rescues the deficits in motor coordination and working memory in both male and female zQ175 mice throughout 15 months of age. Furthermore, VGLUT3 deletion rescues the neuronal loss and promotes the activation of Akt and ERK1/2 cellular pro-survival signaling in the striatum of zQ175 mice of both sexes. Interestingly, the rescue in zQ175:VGLUT3<sup>–/– </sup>mice is accompanied by a reduction in nuclear accumulation of mHTT aggregates with no change in the total aggregate burden in striatal neurons. Collectively, these findings provide novel evidence that VGLUT3 neurotransmission, despite its limited expression, can be a vital contributor to HD progression in a sex-independent fashion and a viable target for HD therapeutics. This study was supported by CIHR grants (PJT-148656, PJT-165967, and PJT-178060) and Funding from Krembil Foundation to Dr. Stephen Ferguson." @default.
- W4377029358 created "2023-05-19" @default.
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- W4377029358 date "2023-05-18" @default.
- W4377029358 modified "2023-09-29" @default.
- W4377029358 title "Genetic deletion of atypical VGLUT3 rescues Huntington’s disease phenotype and neurodegeneration in zQ175 mice" @default.
- W4377029358 doi "https://doi.org/10.1124/jpet.122.185020" @default.
- W4377029358 hasPublicationYear "2023" @default.
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