Huntingtin expression influences spontaneous seizure disorder susceptibility in FVN/B mice

Van Raamsdonk, J.; Al-Shekaili, H.; Wagner, L.; Bredy, T.; Chan, L. L.; Pearson, J.; Schwab, C.; Murphy, Z.; Devon, R. S.; Lu, G.; Kobor, M. S.; Hayden, M. R.; Leavitt, B. R.

doi:10.1101/2022.10.18.512787

bioRxiv · 10.1101/2022.10.18.512787

Huntingtin expression influences spontaneous seizure disorder susceptibility in FVN/B mice

Van Raamsdonk, J.·Al-Shekaili, H.·Wagner, L.·Bredy, T.·Chan, L. L.·Pearson, J.·Schwab, C.·Murphy, Z.·Devon, R. S.·Lu, G.·Kobor, M. S.·Hayden, M. R.·Leavitt, B. R.

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Abstract

Huntington disease (HD) is an adult-onset neurodegenerative disorder that is caused by a trinucleotide CAG repeat expansion in the HTT gene that codes for the protein huntingtin (HTT or Htt in mice). HTT is a multi-functional, ubiquitously expressed protein that is essential for embryonic survival, normal neurodevelopment, and adult brain function. The ability of wild-type HTT to protect neurons against various forms of death raises the possibility that loss of normal HTT function may worsen disease progression in HD. Huntingtin-lowering therapeutics are being evaluated in clinical trials for HD, but concerns have been raised that decreasing wild-type HTT levels may have adverse effects. Here we show that Htt levels modulate the occurrence of an idiopathic seizure disorder that spontaneously occurs in FVB/N mice. These abnormal FVB/N mice demonstrate various cardinal features of mouse models of epilepsy including spontaneous seizures, astrocytosis, neuronal hypertrophy, upregulation of brain-derived neurotrophic factor (BDNF), and sudden seizure-related death. Interestingly, decreasing wild-type Htt levels increased the frequency of this disorder, while over-expression of HTT completely prevented it. Examination of the mechanism underlying huntingtins ability to modulate the frequency of this seizure disorder indicated that over-expression of full length HTT can promote neuronal survival following seizures. Overall, our results demonstrate a protective role for huntingtin in this form of epilepsy and provide a plausible explanation for the observation of seizures in the juvenile form of HD, Lopes-Maciel-Rodan syndrome, and Wolf-Hirschhorn syndrome. Adverse effects caused by altering huntingtin levels has ramifications related to Huntingtin-lowering therapies in development to treat HD.

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Van Raamsdonk, J., Al-Shekaili, H., Wagner, L., Bredy, T., Chan, L. L., Pearson, J., Schwab, C., Murphy, Z., Devon, R. S., Lu, G., Kobor, M. S., Hayden, M. R., Leavitt, B. R.. 2022-10-21. Huntingtin expression influences spontaneous seizure disorder susceptibility in FVN/B mice. https://doi.org/10.1101/2022.10.18.512787

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