title: Pharmacological or Genetic Activation of Hsp70 Protects against Loss of Parkin Function.
abstract: Mutations of parkin are a prevalent genetic contributor to familial Parkinson's disease (PD). As a key regulator of protein and mitochondrial homeostasis, parkin plays a pivotal role in maintaining dopaminergic neuronal survival. However, whereas Drosophila parkin null mutants exhibit prominent parkinsonian features, parkin-deficient mice generally lack an overt phenotype. Here, we found that the expression of Hsp70 along with several other members of the chaperone family is elevated in parkin null mice, suggesting a possible compensatory mechanism for the loss of parkin function in these mice that could have masked their phenotype. Supporting this, we demonstrate that the enhancement of chaperone function induced either pharmacologically via 17-AAG treatment or genetically via Hsp70 overexpression can protect cells against proteolytic and mitochondrial stress in a manner that is similar to that brought about by parkin overexpression. Importantly, we further showed that enhanced chaperone activity can ameliorate the pathological phenotypes in Drosophila parkin null mutants, which suggests the ability of chaperones to phenocopy parkin function. Taken together, our results suggest that Hsp members may act as compensatory factors for parkin loss of function and that the exploitation of these factors may be of potential therapeutic value.
authors.affiliation: Neurodegeneration Research Laboratory, National Neuroscience Institute, Singapore, Singapore.
authors.forename: Cheng-Wu
authors.initials: CW
authors.lastname: Zhang
authors.forename: Henry Basil
authors.initials: HB
authors.lastname: Adeline
authors.forename: Bing-Han
authors.initials: BH
authors.lastname: Chai
authors.forename: Eugenia T E
authors.initials: ET
authors.lastname: Hong
authors.forename: Chee-Hoe
authors.initials: CH
authors.lastname: Ng
authors.forename: Kah-Leong
authors.initials: KL
authors.lastname: Lim
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D016227:Benzoquinones / Q000008:administration & dosage; D045744:Cell Line, Tumor; D004330:Drosophila; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D016227:Benzoquinones; D018840:HSP70 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018696:Neuroprotective Agents; C112765:tanespimycin; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D046988:Proteasome Endopeptidase Complex