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A plant-based mutant huntingtin model-driven discovery of impaired expression of GTPCH and DHFR
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A plant-based mutant huntingtin model-driven discovery of impaired expression of GTPCH and DHFR
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Journal Article
A plant-based mutant huntingtin model-driven discovery of impaired expression of GTPCH and DHFR
2022
Overview
Pathophysiology associated with Huntington’s 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 early polyQ-induced pathogenic events, we expressed Htt exon1 (Htt
ex1
) with a normal (21), or an extended (42 or 63) number of polyQ in tobacco plants. Here, we show that transgenic plants accumulated Htt
ex1
proteins with corresponding polyQ tracts, and mHtt
ex1
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 Htt
ex1
Q63 and unaffected Htt
ex1
Q21 plants showed that the most reduced protein by polyQ63 is a GTP cyclohydrolase I (GTPCH) along with many of its related one-carbon (C
1
) metabolic pathway enzymes. GTPCH is a key enzyme involved in folate biosynthesis in plants and tetrahydrobiopterin (BH
4
) biosynthesis in mammals. Validating studies in 4-week-old R6/2 HD mice expressing a mHtt
ex1
showed reduced levels of GTPCH and dihydrofolate reductase (DHFR, a key folate utilization/alternate BH
4
biosynthesis enzyme), and impaired C
1
and BH
4
metabolism. Our findings from mHtt
ex1
plants and mice reveal impaired expressions of GTPCH and DHFR and may contribute to a better understanding of mHtt-altered C
1
and BH
4
metabolism, and their roles in the pathogenesis of HD.
Publisher
Springer International Publishing,Springer Nature B.V
Subject
/ Animals
/ Biomedical and Life Sciences
/ Carbon
/ Enzymes
/ genetically modified organisms
/ GTP Cyclohydrolase - metabolism
/ Huntingtin Protein - genetics
/ Huntington Disease - metabolism
/ Mice
/ Mutants
/ Original
/ Plants, Genetically Modified
/ Proteins
/ Tetrahydrofolate Dehydrogenase - metabolism
/ Tobacco
