title: Geldanamycin induces Hsp70 and prevents alpha-synuclein aggregation and toxicity in vitro.
abstract: Geldanamycin (GA) is a naturally occurring benzoquinone ansamycin that induces heat shock protein 70 (Hsp70). GA has been shown to reduce alpha-synuclein induced neurotoxicity in a fly model of Parkinson's disease. We have previously shown that heat shock proteins can prevent alpha-synuclein aggregation and protect against alpha-synuclein induced toxicity in human H4 neuroglioma cells. Here, we hypothesize that GA treatment will reduce alpha-synuclein aggregation and prevent alpha-synuclein induced toxicity and we show that GA can induce Hsp70 in a time- and concentration-dependent manner in H4 cells. Pretreatment with 200nM GA 24h prior to transfection prevented alpha-synuclein aggregation and protected against toxicity. Treatment of cells with pre-existing inclusions with GA did not result in a reduction in the number of cells containing inclusions, suggesting that upregulation of Hsp70 is not sufficient to remove established inclusions. Similarly, Western blot analysis demonstrated that GA treatment could dramatically reduce both total alpha-synuclein and high molecular weight alpha-synuclein aggregates. Taken together, these data suggest that GA is effective in preventing alpha-synuclein aggregation and may represent a pharmacological intervention to therapeutically increase expression of molecular chaperone proteins to treat neurodegenerative diseases where aggregation is central to the pathogenesis.
authors.affiliation: Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA. pmclean@partners.org
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: McLean
authors.forename: Jochen
authors.initials: J
authors.lastname: Klucken
authors.forename: Youngah
authors.initials: Y
authors.lastname: Shin
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D016227:Benzoquinones; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D002479:Inclusion Bodies; D047029:Lactams, Macrocyclic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology* / Q000627:therapeutic use; D051843:Synucleins; D015854:Up-Regulation; D051844:alpha-Synuclein
chemical_list: D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D018840:HSP70 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D009419:Nerve Tissue Proteins; D011809:Quinones; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; C001277:geldanamycin