Critical role of the proline-rich region in Huntingtin for aggregation and cytotoxicity in yeast.
Nine neurodegenerative diseases, such as Huntington, are caused by a polyglutamine (poly(Q)) expansion in otherwise unrelated proteins. Although poly(Q) expansion causes aggregation of the affected proteins, the protein context might determine the selective neuronal vulnerability found in each disease. Here we have report that, although expression of Huntingtin derivatives with a pathological poly(Q) expansion are innocuous in yeast, deletion of the flanking proline-rich region alters the shape and number of poly(Q) inclusions and unmasks toxic properties. Strikingly, deletion of Hsp104 increases the size of inclusions formed by expanded poly(Q) lacking the proline-rich region and abolishes toxicity. Overexpression of the chaperones Hsp104 or Hsp70 rescues growth defects in affected cells without resolving inclusions. However, aggregates formed by nontoxic Huntingtin derivatives or by toxic derivatives cured by chaperones are physically distinct from aggregates formed by toxic proteins. This study identifies the proline-rich region in Huntingtin as a profound cis-acting modulator of expanded poly(Q) toxicity and distinguishes between aggregates of toxic or non-toxic proteins.
Dehay
Benjamin
B
Laboratoire de Génétique Moléculaire, CNRS UMR8541, Ecole Normale Supérieure, 46 rue d'Ulm, 75230 Paris Cedex 05, France.
Bertolotti
Anne
A
D002499:Centrifugation, Density Gradient; D005561:Formates / Q000737:chemistry; D017353:Gene Deletion; D049452:Green Fluorescent Proteins / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry; D006360:Heat-Shock Proteins / Q000737:chemistry; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics; D008856:Microscopy, Fluorescence; D018832:Molecular Chaperones / Q000737:chemistry; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000502:physiology; D009687:Nuclear Proteins / Q000737:chemistry* / Q000502:physiology; D010455:Peptides / Q000737:chemistry; D011392:Proline / Q000737:chemistry*; D011485:Protein Binding; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry; D013395:Sucrose / Q000494:pharmacology
D005561:Formates; D018840:HSP70 Heat-Shock Proteins; C086055:HTT protein, human; D006360:Heat-Shock Proteins; D000071058:Huntingtin Protein; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D029701:Saccharomyces cerevisiae Proteins; C030544:formic acid; C070972:HsP104 protein, S cerevisiae; D049452:Green Fluorescent Proteins; C097188:polyglutamine; D013395:Sucrose; D011392:Proline