title: Small heat shock proteins protect against alpha-synuclein-induced toxicity and aggregation.
abstract: Protein misfolding and inclusion formation are common events in neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD) or Huntington's disease (HD). Alpha-synuclein (aSyn) is the main protein component of inclusions called Lewy bodies (LB) which are pathognomic of PD, Dementia with Lewy bodies (DLB), and other diseases collectively known as LB diseases. Heat shock proteins (HSPs) are one class of the cellular quality control system that mediate protein folding, remodeling, and even disaggregation. Here, we investigated the role of the small heat shock proteins Hsp27 and alphaB-crystallin, in LB diseases. We demonstrate, via quantitative PCR, that Hsp27 messenger RNA levels are approximately 2-3-fold higher in DLB cases compared to control. We also show a corresponding increase in Hsp27 protein levels. Furthermore, we found that Hsp27 reduces aSyn-induced toxicity by approximately 80% in a culture model while alphaB-crystallin reduces toxicity by approximately 20%. In addition, intracellular inclusions were immunopositive for endogenous Hsp27, and overexpression of this protein reduced aSyn aggregation in a cell culture model.
authors.affiliation: Alzheimer's Research Unit, MassGeneral Institute for Neurodegenerative Disease, MGH, Harvard Medical School, Charlestown, MA 02129, USA. touteir@partners.org
authors.forename: Tiago Fleming
authors.initials: TF
authors.lastname: Outeiro
authors.forename: Jochen
authors.initials: J
authors.lastname: Klucken
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Strathearn
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Paul
authors.initials: P
authors.lastname: Nguyen
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Rochet
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: McLean
mesh_terms: D000818:Animals; D002449:Cell Aggregation / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism*; D050888:Heat-Shock Proteins, Small / Q000378:metabolism; D006801:Humans; D020961:Lewy Body Disease / Q000378:metabolism* / Q000473:pathology*; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D009498:Neurotoxins / Q000494:pharmacology; D051381:Rats; D038203:alpha-Crystallin B Chain / Q000378:metabolism*; D051844:alpha-Synuclein / Q000494:pharmacology*
chemical_list: D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D050888:Heat-Shock Proteins, Small; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D009498:Neurotoxins; D038203:alpha-Crystallin B Chain; D051844:alpha-Synuclein