Small heat shock proteins protect against alpha-synuclein-induced toxicity and aggregation.
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.
Outeiro
Tiago Fleming
TF
Alzheimer's Research Unit, MassGeneral Institute for Neurodegenerative Disease, MGH, Harvard Medical School, Charlestown, MA 02129, USA. touteir@partners.org
Klucken
Jochen
J
Strathearn
Katherine E
KE
Liu
Fang
F
Nguyen
Paul
P
Rochet
Jean-Christophe
JC
Hyman
Bradley T
BT
McLean
Pamela J
PJ
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*
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