HSP90-incorporating chaperome networks as biosensor for disease-related pathways in patient-specific midbrain dopamine neurons

Sarah Kishinevsky, Tai Wang, Anna Rodina, Sun Young Chung, Chao Xu, John Philip, Tony Taldone, Suhasini Joshi, Mary L. Alpaugh, Alexander Bolaender, Simon Gutbier, Davinder Sandhu, Faranak Fattahi, Bastian Zimmer, Smit K. Shah, Elizabeth Chang, Carmen Inda, John Koren, Nathalie G. Saurat, Marcel LeistSteven S. Gross, Venkatraman E. Seshan, Christine Klein, Mark J. Tomishima, Hediye Erdjument-Bromage, Thomas A. Neubert, Ronald C. Henrickson, Gabriela Chiosis, Lorenz Studer

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Environmental and genetic risk factors contribute to Parkinson’s Disease (PD) pathogenesis and the associated midbrain dopamine (mDA) neuron loss. Here, we identify early PD pathogenic events by developing methodology that utilizes recent innovations in human pluripotent stem cells (hPSC) and chemical sensors of HSP90-incorporating chaperome networks. We show that events triggered by PD-related genetic or toxic stimuli alter the neuronal proteome, thereby altering the stress-specific chaperome networks, which produce changes detected by chemical sensors. Through this method we identify STAT3 and NF-κB signaling activation as examples of genetic stress, and phospho-tyrosine hydroxylase (TH) activation as an example of toxic stress-induced pathways in PD neurons. Importantly, pharmacological inhibition of the stress chaperome network reversed abnormal phospho-STAT3 signaling and phospho-TH-related dopamine levels and rescued PD neuron viability. The use of chemical sensors of chaperome networks on hPSC-derived lineages may present a general strategy to identify molecular events associated with neurodegenerative diseases.

Original languageEnglish (US)
Article number4345
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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