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; Lorenz Studer

doi:10.1038/s41467-018-06486-6

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

^*Corresponding author for this work

Institute of Neurogenetics

11 Citations (Scopus)

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 language	English
Article number	4345
Journal	Nature Communications
Volume	9
Issue number	1
ISSN	1751-8628
DOIs	https://doi.org/10.1038/s41467-018-06486-6
Publication status	Published - 01.12.2018

Funding

We thank the D. Krainc lab for providing the PD iPSC lines, Elizabeth Calder, Sonja Kriks, Justine Miller, Jae-Won Shim, Julius Steinbeck, for technical advice, support and data interpretation. We further thank A. Rajadhyaksha and D. Eliezer for critical discussions on the project. The work was supported in part by the National Institute of Neurological Disorders and Stroke (NINDS) grant NS052671 and NYSTEM contract C028503 to L.S. and by R01 CA172546, U01 AG032969, R56 AG061869, P01 CA186866, P30 CA08748, P50 CA192937 and R21 AG028811 from the NIH and the Coins for Alzheimer’s Research Trust (CART) Fund to G.C. This work was further supported by grants from the Parkinson’s disease and Jeffry and Barbara Picower Foundations, a core grant P30 CA08748 from the NIH, and the BMBF project NeuriTox. S.K. was supported by an NRSA F31 (NIH) pre-doctoral fellowship from NINDS, and T.W. by a Lymphoma Research Foundation postdoctoral fellow grant. C.K. is supported by the DFG (FOR2488).

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Research Area: Medical Genetics

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Kishinevsky, S., Wang, T., Rodina, A., Chung, S. Y., Xu, C., Philip, J., Taldone, T., Joshi, S., Alpaugh, M. L., Bolaender, A., Gutbier, S., Sandhu, D., Fattahi, F., Zimmer, B., Shah, S. K., Chang, E., Inda, C., Koren, J., Saurat, N. G., ... Studer, L. (2018). HSP90-incorporating chaperome networks as biosensor for disease-related pathways in patient-specific midbrain dopamine neurons. Nature Communications, 9(1), Article 4345. https://doi.org/10.1038/s41467-018-06486-6

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

abstract = "Environmental and genetic risk factors contribute to Parkinson{\textquoteright}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.",

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

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doi = "10.1038/s41467-018-06486-6",

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Kishinevsky, S, Wang, T, Rodina, A, Chung, SY, Xu, C, Philip, J, Taldone, T, Joshi, S, Alpaugh, ML, Bolaender, A, Gutbier, S, Sandhu, D, Fattahi, F, Zimmer, B, Shah, SK, Chang, E, Inda, C, Koren, J, Saurat, NG, Leist, M, Gross, SS, Seshan, VE, Klein, C, Tomishima, MJ, Erdjument-Bromage, H, Neubert, TA, Henrickson, RC, Chiosis, G & Studer, L 2018, 'HSP90-incorporating chaperome networks as biosensor for disease-related pathways in patient-specific midbrain dopamine neurons', Nature Communications, vol. 9, no. 1, 4345. https://doi.org/10.1038/s41467-018-06486-6

TY - JOUR

T1 - HSP90-incorporating chaperome networks as biosensor for disease-related pathways in patient-specific midbrain dopamine neurons

AU - Kishinevsky, Sarah

AU - Wang, Tai

AU - Rodina, Anna

AU - Chung, Sun Young

AU - Xu, Chao

AU - Philip, John

AU - Taldone, Tony

AU - Joshi, Suhasini

AU - Alpaugh, Mary L.

AU - Bolaender, Alexander

AU - Gutbier, Simon

AU - Sandhu, Davinder

AU - Fattahi, Faranak

AU - Zimmer, Bastian

AU - Shah, Smit K.

AU - Chang, Elizabeth

AU - Inda, Carmen

AU - Koren, John

AU - Saurat, Nathalie G.

AU - Leist, Marcel

AU - Gross, Steven S.

AU - Seshan, Venkatraman E.

AU - Klein, Christine

AU - Tomishima, Mark J.

AU - Erdjument-Bromage, Hediye

AU - Neubert, Thomas A.

AU - Henrickson, Ronald C.

AU - Chiosis, Gabriela

AU - Studer, Lorenz

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85055076176

U2 - 10.1038/s41467-018-06486-6

DO - 10.1038/s41467-018-06486-6

M3 - Journal articles

C2 - 30341316

AN - SCOPUS:85055076176

SN - 1751-8628

VL - 9

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4345

ER -

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

Abstract

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UN SDGs

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