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Nat Commun. 2018 Oct 19;9(1):4345. doi: 10.1038/s41467-018-06486-6.

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

Author information

1
The Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 256, New York, NY, 10065, USA.
2
Developmental Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 256, New York, NY, 10065, USA.
3
Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
4
Neuroscience Graduate Program of Weill Cornell Graduate School of Biomedical Sciences, Weill Cornell Medical College, 1300 York Avenue, Box 65, New York, NY, 10065, USA.
5
Proteomics Core Facility, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
6
Department of Molecular and Cellular Biosciences, Rowan University, 1275 York Avenue, Glassboro, NJ, 08028, USA.
7
Doerenkamp-Zbinden Chair for In Vitro Toxicology and Biomedicine, University of Konstanz, Konstanz, 78464, Germany.
8
Department of Pharmacology, Weill Cornell College of Medicine, 1300 York Avenue, New York, NY, 10065, USA.
9
Hostos Community College, City University of New York, Bronx, NY, 10453, USA.
10
Department of Biochemistry, University of Notre Dame, Notre Dame, IN, 46556, USA.
11
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, 10017, USA.
12
Institute of Neurogenetics, University of Lübeck, Lübeck, 23538, Germany.
13
SKI Stem Cell Research Facility, 1275 York Avenue, Sloan Kettering Institute, New York, NY, 10065, USA.
14
Department of Cell Biology, NYU School of Medicine, New York, NY, 10016, USA.
15
Kimmel Center for Biology and Medicine at the Skirball Institute, NYU School of Medicine, New York, NY, 10016, USA.
16
Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. chiosisg@mskcc.org.
17
Department of Medicine, Memorial Hospital, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. chiosisg@mskcc.org.

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.

PMID:
30341316
PMCID:
PMC6195591
DOI:
10.1038/s41467-018-06486-6
[Indexed for MEDLINE]
Free PMC Article

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