RT Journal Article
SR Electronic
T1 Mutant Huntingtin Is Cleared from the Brain via Active Mechanisms in Huntington Disease
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 780
OP 796
DO 10.1523/JNEUROSCI.1865-20.2020
VO 41
IS 4
A1 Nicholas S. Caron
A1 Raul Banos
A1 Christopher Yanick
A1 Amirah E. Aly
A1 Lauren M. Byrne
A1 Ethan D. Smith
A1 Yuanyun Xie
A1 Stephen E.P. Smith
A1 Nalini Potluri
A1 Hailey Findlay Black
A1 Lorenzo Casal
A1 Seunghyun Ko
A1 Daphne Cheung
A1 Hyeongju Kim
A1 Ihn Sik Seong
A1 Edward J. Wild
A1 Ji-Joon Song
A1 Michael R. Hayden
A1 Amber L. Southwell
YR 2021
UL http://www.jneurosci.org/content/41/4/780.abstract
AB 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.SIGNIFICANCE STATEMENT: Changes in CSF mutant huntingtin (mHTT) are being used as an exploratory endpoint in HTT lowering clinical trials for the treatment of Huntington disease (HD). Recently, it was demonstrated that intrathecal administration of a HTT lowering agent leads to dose-dependent reduction of CSF mHTT in HD patients. However, little is known about how HTT, an intracellular protein, reaches the extracellular space and ultimately the CSF. Our findings that HTT enters CSF by both passive release and active secretion followed by glymphatic clearance may have significant implications for interpretation of treatment-induced changes of CSF mHTT in clinical trials for HD.