A plant-based mutant huntingtin model-driven discovery of impaired expression of GTPCH and DHFR

Abstract

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 (Httex1) with a normal (21), or an extended (42 or 63) number of polyQ in tobacco plants. Here, we show that transgenic plants accumulated Httex1 proteins with corresponding polyQ tracts, and 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 reduced protein by polyQ63 is a GTP cyclohydrolase I (GTPCH) along with many of 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 metabolism. Our findings from mHttex1 plants and mice reveal impaired expressions of GTPCH and DHFR and may contribute to a better understanding of mHtt-altered C1 and BH4 metabolism, and their roles in the pathogenesis of HD.

Techno-Functions and Safety Concerns of Plant-Based Peptides in Food Matrices

“…With this method, genomes encoding particular peptide sequences are inserted into microorganisms, causing them to produce the required peptides throughout their cultivation. Therefore, the peptide characteristics can be managed and customized. − …”

“…Controlled production, the potential for customization Regulatory concerns, ethical considerations. Leite et al, 60 Jackson et al, 61 Hung et al 62 Microwave-assisted extraction The plant material is heated with microwaves to promote the release of peptides.…”

Current Advances of Plant-Based Vaccines for Neurodegenerative Diseases

“…It is worth emphasizing that most of the reported plant-made vaccines for NDDs are centered on AD, PD, and MS; hence, further investigations are required to produce plant-based antigens for other classes of NDDs, i.e., ALS, HD, FTD, DLB, and prion diseases. Remarkably, Hung et al [ 149 ] expressed huntingtin exon1 (Htt ex1 , a protein involved in HD pathogenesis) with abnormally long polyglutamine (polyQ) tracts in tobacco and examined the phenotypic impact of the aberrant protein within the plant. Thus, this innovative approach could be harnessed to promote plant-derived vaccines for HD.…”