title: Natural osmolytes remodel the aggregation pathway of mutant huntingtin exon 1.
abstract: In response to stress small organic compounds termed osmolytes are ubiquitously accumulated in all cell types to regulate the intracellular solvent quality and to counteract the deleterious effect on the stability and function of cellular proteins. Given the evidence that destabilization of the native state of a protein either by mutation or by environmental changes triggers the aggregation in the neurodegenerative pathologies, the modulation of the intracellular solute composition with osmolytes is an attractive strategy to stabilize an aggregating protein. Here we report the effect of three natural osmolytes on the in vivo and in vitro aggregation landscape of huntingtin exon 1 implicated in the Huntington's disease. Trimethylamine N-oxide (TMAO) and proline redirect amyloid fibrillogenesis of the pathological huntingtin exon 1 to nonamyloidogenic amorphous assemblies via two dissimilar molecular mechanisms. TMAO causes a rapid formation of bulky amorphous aggregates with minimally exposed surface area, whereas proline solubilizes the monomer and suppresses the accumulation of early transient aggregates. Conversely, glycine-betaine enhances fibrillization in a fashion reminiscent of the genesis of functional amyloids. Strikingly, none of the natural osmolytes can completely abrogate the aggregate formation; however, they redirect the amyloidogenesis into alternative, nontoxic aggregate species. Our study reveals new insights into the complex interactions of osmoprotectants with polyQ aggregates.
authors.affiliation: Department of Biochemistry, Institute of Biochemistry and Biology, University of Potsdam, Karl-Liebknecht-Strasse 24-25, 14467 Potsdam, Germany.
authors.forename: Tejas
authors.initials: T
authors.lastname: Borwankar
authors.forename: Christoph
authors.initials: C
authors.lastname: Röthlein
authors.forename: Gong
authors.initials: G
authors.lastname: Zhang
authors.forename: Anne
authors.initials: A
authors.lastname: Techen
authors.forename: Carsten
authors.initials: C
authors.lastname: Dosche
authors.forename: Zoya
authors.initials: Z
authors.lastname: Ignatova
mesh_terms: D000818:Animals; D001622:Betaine / Q000494:pharmacology; D001688:Biological Products / Q000494:pharmacology*; D005091:Exons; D008744:Methylamines / Q000494:pharmacology; D050505:Mutant Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D009995:Osmosis / Q000187:drug effects*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011392:Proline / Q000494:pharmacology; D055503:Protein Multimerization / Q000187:drug effects*; D020836:Protein Structure, Quaternary; D012995:Solubility
chemical_list: D001688:Biological Products; D008744:Methylamines; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; C097188:polyglutamine; D001622:Betaine; D011392:Proline; C005855:trimethyloxamine