Mutant huntingtin exon-1 impaired GTPCH and DHFR expression in plants and mice

Hung, C.-Y.; Zhu, C.-S.; Kittur, F. S.; He, M.; Arning, E.; Zhang, J.; Johnson, A. J.; Jawa, G. S.; Thomas, M. D.; Ding, T. T.; Xie, J.

doi:10.1101/2022.05.18.492514

bioRxiv · 10.1101/2022.05.18.492514

Mutant huntingtin exon-1 impaired GTPCH and DHFR expression in plants and mice

Hung, C.-Y.·Zhu, C.-S.·Kittur, F. S.·He, M.·Arning, E.·Zhang, J.·Johnson, A. J.·Jawa, G. S.·Thomas, M. D.·Ding, T. T.·Xie, J.

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Abstract

Pathophysiology associated with Huntingtons disease (HD) has been studied extensively in various cell and animal models since the 1993 discovery of the mutant huntingtin (mHtt) with abnormally expanded polyglutamine (polyQ) tracts as the causative factor. However, the sequence of early pathophysiological events leading to HD still remains elusive. To gain new insights into the polyQ-induced early pathogenic events, we expressed Htt exon1 (Httex1) with a normal (21), or an extended (42 or 63) number of polyQ in tobacco plants, which lack an Htt ortholog to avoid any associated effects from endogenous Htt. Here, we show that transgenic plants accumulated Httex1 proteins with corresponding polyQ tracts, and that mHttex1 induced protein aggregation and affected plant growth, especially root and root hair development, in a polyQ length-dependent manner. Quantitative proteomic analysis of young roots from severely affected Httex1Q63 and unaffected Httex1Q21 plants showed that the most impaired protein by polyQ63 is a GTP cyclohydrolase I (GTPCH) along with many its related one-carbon (C1) metabolic pathway enzymes. GTPCH is a key enzyme involved in folate biosynthesis in plants and tetrahydrobiopterin (BH4) biosynthesis in mammals. Validating studies in 4-week-old R6/2 HD mice expressing a mHttex1 showed reduced levels of GTPCH and dihydrofolate reductase (DHFR, a key folate utilization/alternate BH4 biosynthesis enzyme), and impaired C1 and BH4 metabolisms. Our findings from mHttex1 plants and mice reveal impaired expressions of GTPCH and DHFR and contribute to a better understanding of mHtt-altered C1 metabolism and C1 interconnected BH4 metabolism leading to the pathogenesis of HD.

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Hung, C.-Y., Zhu, C.-S., Kittur, F. S., He, M., Arning, E., Zhang, J., Johnson, A. J., Jawa, G. S., Thomas, M. D., Ding, T. T., Xie, J.. 2022-05-18. Mutant huntingtin exon-1 impaired GTPCH and DHFR expression in plants and mice. https://doi.org/10.1101/2022.05.18.492514

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