title: Chaperone proteostasis in Parkinson's disease: stabilization of the Hsp70/alpha-synuclein complex by Hip.
abstract: The ATP-dependent protein chaperone heat-shock protein 70 (Hsp70) displays broad anti-aggregation functions and has a critical function in preventing protein misfolding pathologies. According to in vitro and in vivo models of Parkinson's disease (PD), loss of Hsp70 activity is associated with neurodegeneration and the formation of amyloid deposits of alpha-synuclein (alphaSyn), which constitute the intraneuronal inclusions in PD patients known as Lewy bodies. Here, we show that Hsp70 depletion can be a direct result of the presence of aggregation-prone polypeptides. We show a nucleotide-dependent interaction between Hsp70 and alphaSyn, which leads to the aggregation of Hsp70, in the presence of ADP along with alphaSyn. Such a co-aggregation phenomenon can be prevented in vitro by the co-chaperone Hip (ST13), and the hypothesis that it might do so also in vivo is supported by studies of a Caenorhabditis elegans model of alphaSyn aggregation. Our findings indicate that a decreased expression of Hip could facilitate depletion of Hsp70 by amyloidogenic polypeptides, impairing chaperone proteostasis and stimulating neurodegeneration.
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge, UK. cintia.roodveldt@cabimer.es
authors.forename: Cintia
authors.initials: C
authors.lastname: Roodveldt
authors.forename: Carlos W
authors.initials: CW
authors.lastname: Bertoncini
authors.forename: August
authors.initials: A
authors.lastname: Andersson
authors.forename: Annemieke T
authors.initials: AT
authors.lastname: van der Goot
authors.forename: Shang-Te
authors.initials: ST
authors.lastname: Hsu
authors.forename: Rafael
authors.initials: R
authors.lastname: Fernández-Montesinos
authors.forename: Jannie
authors.initials: J
authors.lastname: de Jong
authors.forename: Tjakko J
authors.initials: TJ
authors.lastname: van Ham
authors.forename: Ellen A
authors.initials: EA
authors.lastname: Nollen
authors.forename: David
authors.initials: D
authors.lastname: Pozo
authors.forename: John
authors.initials: J
authors.lastname: Christodoulou
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
mesh_terms: D000255:Adenosine Triphosphate / Q000502:physiology; D000682:Amyloid / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000254:growth & development / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D045744:Cell Line, Tumor; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D018832:Molecular Chaperones; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism / Q000517:prevention & control; D010300:Parkinson Disease / Q000209:etiology / Q000378:metabolism*; D010455:Peptides / Q000037:antagonists & inhibitors / Q000502:physiology; D017510:Protein Folding; D055550:Protein Stability; D051381:Rats; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D051844:alpha-Synuclein / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000682:Amyloid; D002352:Carrier Proteins; D018840:HSP70 Heat-Shock Proteins; D018832:Molecular Chaperones; D046912:Multiprotein Complexes; D010455:Peptides; C522797:St13 protein, rat; D025521:Tumor Suppressor Proteins; D051844:alpha-Synuclein; D000255:Adenosine Triphosphate