title: Cellular toxicity of yeast prion protein Rnq1 can be modulated by N-terminal wild type huntingtin.
abstract: Aggregation of the N-terminal human mutant huntingtin and the consequent toxicity in the yeast model of Huntington's disease (HD) requires the presence of Rnq1 protein (Rnq1p) in its prion conformation [RNQ1(+)]. The understanding of interaction of wild-type huntingtin (wt-Htt) with the amyloidogenic prion has some gaps. In this work, we show that N-terminal fragment of wt-Htt (N-wt-Htt) ameliorated the toxic effect of [RNQ1(+)] depending on expression levels of both proteins. When the expression of N-wt-Htt was high, it increased the expression and delayed the aggregation of [RNQ1(+)]. As the expression of N-wt-Htt was reduced, it formed high molecular weight aggregates along with the prion. Even when sequestered by [RNQ1(+)], the beneficial effect of N-wt-Htt on expression of Rnq1p and on cell survival was evident. Huntingtin protein ameliorated toxicity due to the prion protein [RNQ1(+)] in yeast cells in a dose-dependent manner, resulting in increase in cell survival, hinting at its probable role as a component of the proteostasis network of the cell. Taking into account the earlier reports of the beneficial effect of expression of N-wt-Htt on the aggregation of mutant huntingtin, the function of wild-type huntingtin as an inhibitor of protein aggregation in the cell needs to be explored.
authors.affiliation: Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab 160062, India.
authors.forename: Ratnika
authors.initials: R
authors.lastname: Sethi
authors.affiliation: Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab 160062, India.
authors.forename: Vishal
authors.initials: V
authors.lastname: Patel
authors.affiliation: Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab 160062, India.
authors.forename: Aliabbas A
authors.initials: AA
authors.lastname: Saleh
authors.affiliation: Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab 160062, India. Electronic address: ipsita@niper.ac.in.
authors.forename: Ipsita
authors.initials: I
authors.lastname: Roy
mesh_terms: D002470:Cell Survival / Q000502:physiology; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D011328:Prions / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D011328:Prions; C404807:RNQ1 protein, S cerevisiae; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins
keywords: Chaperone; Huntingtin; Prions; Protein aggregation