title: Effect of endogenous Hsp104 chaperone in yeast models of sporadic and familial Parkinson's disease.
abstract: Molecular chaperones constitute a major component of the cellular stress response machinery in neurodegenerative diseases, many of which are characterized by the misfolding and aggregation of endogenous cellular proteins into generic amyloid macrostructures. Heterologous expression of the yeast protein remodelling factor Hsp104 has been proposed as a possible therapeutic approach in such disease conditions. Hsp104 is unique in its ability to act as a protein 'disaggregase' by removing smaller units from amyloid fibrils and has no homologue in metazoa. The effect of Hsp104 is strongly modulated by its expression level. We show that at endogenous levels, the presence of Hsp104 has a deleterious effect on protein aggregation in two different strains of yeast. Overexpression of wild-type and mutant human α-synuclein in a well-validated yeast model of Parkinson's disease and in an isogenic Hsp104-deleted strain resulted in lower oxidative stress and reduced damage to cellular proteins in the latter case. This translated to lower cytotoxicity and increased cell viability. Endocytotic defect caused due to aggregation of α-syuclein was also rescued in cells lacking Hsp104. Our results show that the effect of overexpression of a chaperone on protein misfolding/aggregation cannot be predicted from its function in the host expression platform.
authors.affiliation: Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab 160 062, India.
authors.forename: Vamshidhar R
authors.initials: VR
authors.lastname: Gade
authors.affiliation: Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab 160 062, India.
authors.forename: Jay
authors.initials: J
authors.lastname: Kardani
authors.affiliation: Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab 160 062, India. Electronic address: ipsita@niper.ac.in.
authors.forename: Ipsita
authors.initials: I
authors.lastname: Roy
mesh_terms: D004705:Endocytosis / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D018613:Microscopy, Confocal; D008957:Models, Genetic; D009154:Mutation; D018384:Oxidative Stress / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism; D011328:Prions / Q000235:genetics / Q000378:metabolism; D066329:Protein Aggregates / Q000235:genetics; D011726:Pyridinium Compounds / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
chemical_list: C092350:FM 4-64; D006360:Heat-Shock Proteins; D011328:Prions; D066329:Protein Aggregates; D011726:Pyridinium Compounds; D000644:Quaternary Ammonium Compounds; C404807:RNQ1 protein, S cerevisiae; C497604:SNCA protein, human; D029701:Saccharomyces cerevisiae Proteins; D051844:alpha-Synuclein; C070972:HsP104 protein, S cerevisiae; D049452:Green Fluorescent Proteins
keywords: Amyloid fibrils; Chaperone; Hsp104; Parkinson's disease; Protein aggregation; α-Synuclein