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 Leist, Steven S. Gross, Venkatraman E. Seshan, Christine Klein, Mark J. Tomishima, Hediye Erdjument-Bromage, Thomas A. Neubert, Ronald C. Henrickson, Gabriela Chiosis () and Lorenz Studer ()
Additional contact information
Sarah Kishinevsky: Memorial Sloan Kettering Cancer Center
Tai Wang: Memorial Sloan Kettering Cancer Center
Anna Rodina: Memorial Sloan Kettering Cancer Center
Sun Young Chung: Memorial Sloan Kettering Cancer Center
Chao Xu: Memorial Sloan Kettering Cancer Center
John Philip: Memorial Sloan Kettering Cancer Center
Tony Taldone: Memorial Sloan Kettering Cancer Center
Suhasini Joshi: Memorial Sloan Kettering Cancer Center
Mary L. Alpaugh: Memorial Sloan Kettering Cancer Center
Alexander Bolaender: Memorial Sloan Kettering Cancer Center
Simon Gutbier: University of Konstanz
Davinder Sandhu: Weill Cornell College of Medicine
Faranak Fattahi: Memorial Sloan Kettering Cancer Center
Bastian Zimmer: Memorial Sloan Kettering Cancer Center
Smit K. Shah: Memorial Sloan Kettering Cancer Center
Elizabeth Chang: Memorial Sloan Kettering Cancer Center
Carmen Inda: Memorial Sloan Kettering Cancer Center
John Koren: Memorial Sloan Kettering Cancer Center
Nathalie G. Saurat: Memorial Sloan Kettering Cancer Center
Marcel Leist: University of Konstanz
Steven S. Gross: Weill Cornell College of Medicine
Venkatraman E. Seshan: Memorial Sloan Kettering Cancer Center
Christine Klein: University of Lübeck
Mark J. Tomishima: Memorial Sloan Kettering Cancer Center
Hediye Erdjument-Bromage: NYU School of Medicine
Thomas A. Neubert: NYU School of Medicine
Ronald C. Henrickson: Memorial Sloan Kettering Cancer Center
Gabriela Chiosis: Memorial Sloan Kettering Cancer Center
Lorenz Studer: Memorial Sloan Kettering Cancer Center

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06486-6

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