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Mutant Huntingtin Is Cleared from the Brain via Active Mechanisms in Huntington Disease

Caron, N; Banos, R; Yanick, C; Aly, A; Byrne, L; Smith, E; Xie, Y; ... Southwell, A; + view all (2021) Mutant Huntingtin Is Cleared from the Brain via Active Mechanisms in Huntington Disease. Journal of Neuroscience , 41 (4) pp. 780-796. 10.1523/JNEUROSCI.1865-20.2020. Green open access

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Abstract

Huntington disease (HD) is a neurodegenerative disease caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene. Therapeutics that lower HTT have shown preclinical promise and are being evaluated in clinical trials. However, clinical assessment of brain HTT lowering presents challenges. We have reported that mutant HTT (mHTT) in the CSF of HD patients correlates with clinical measures, including disease burden as well as motor and cognitive performance. We have also shown that lowering HTT in the brains of HD mice results in correlative reduction of mHTT in the CSF, prompting the use of this measure as an exploratory marker of target engagement in clinical trials. In this study, we investigate the mechanisms of mHTT clearance from the brain in adult mice of both sexes to elucidate the significance of therapy-induced CSF mHTT changes. We demonstrate that, although neurodegeneration increases CSF mHTT concentrations, mHTT is also present in the CSF of mice in the absence of neurodegeneration. Importantly, we show that secretion of mHTT from cells in the CNS followed by glymphatic clearance from the extracellular space contributes to mHTT in the CSF. Furthermore, we observe secretion of wild type HTT from healthy control neurons, suggesting that HTT secretion is a normal process occurring in the absence of pathogenesis. Overall, our data support both passive release and active clearance of mHTT into CSF, suggesting that its treatment-induced changes may represent a combination of target engagement and preservation of neurons.

Type: Article
Title: Mutant Huntingtin Is Cleared from the Brain via Active Mechanisms in Huntington Disease
Open access status: An open access version is available from UCL Discovery
DOI: 10.1523/JNEUROSCI.1865-20.2020
Publisher version: https://doi.org/10.1523/JNEUROSCI.1865-20.2020
Language: English
Additional information: This is the published version of record. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10116115
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