Identification and rescue of α-synuclein toxicity in Parkinson patient-derived neurons

Chee Yeun Chung, Vikram Khurana, Pavan K. Auluck, Daniel F. Tardiff, Joseph R. Mazzulli, Frank Soldner, Valeriya Baru, Yali Lou, Yelena Freyzon, Sukhee Cho, Alison E. Mungenast, Julien Muffat, Maisam Mitalipova, Michael D. Pluth, Nathan T. Jui, Birgitt Schul̈e, Stephen J. Lippard, Li Huei Tsai, Dimitri Krainc, Stephen L. Buchwald & 2 others Rudolf Jaenisch, Susan Lindquist*

*Corresponding author for this work

Research output: Contribution to journalArticle

240 Citations (Scopus)

Abstract

The induced pluripotent stem (iPS) cell field holds promise for in vitro disease modeling. However, identifying innate cellular pathologies, particularly for age-related neurodegenerative diseases, has been challenging. Here, we exploited mutation correction of iPS cells and conserved proteotoxic mechanisms from yeast to humans to discover and reverse phenotypic responses to a-synuclein (asyn), a key protein involved in Parkinson 's disease (PD). We generated cortical neurons from iPS cells of patients harboring asyn mutations, who are at high risk of developing PD dementia. Genetic modifiers from unbiased screens in a yeast model of asyn toxicity led to identification of early pathogenic phenotypes in patient neurons. These included nitrosative stress, accumulation of endoplasmic reticulum (ER)-associated degradation substrates, and ER stress. A small molecule identified in a yeast screen (NAB2), and the ubiquitin ligase Nedd4 it affects, reversed pathologic phenotypes in these neurons.

Original languageEnglish (US)
Pages (from-to)983-987
Number of pages5
JournalScience
Volume342
Issue number6161
DOIs
StatePublished - Jan 1 2013

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Synucleins
Induced Pluripotent Stem Cells
Yeasts
Neurons
Parkinson Disease
Endoplasmic Reticulum-Associated Degradation
Phenotype
Mutation
Endoplasmic Reticulum Stress
Ligases
Ubiquitin
Neurodegenerative Diseases
Dementia
Pathology
Proteins

ASJC Scopus subject areas

  • General

Cite this

Chung, C. Y., Khurana, V., Auluck, P. K., Tardiff, D. F., Mazzulli, J. R., Soldner, F., ... Lindquist, S. (2013). Identification and rescue of α-synuclein toxicity in Parkinson patient-derived neurons. Science, 342(6161), 983-987. https://doi.org/10.1126/science.1245296
Chung, Chee Yeun ; Khurana, Vikram ; Auluck, Pavan K. ; Tardiff, Daniel F. ; Mazzulli, Joseph R. ; Soldner, Frank ; Baru, Valeriya ; Lou, Yali ; Freyzon, Yelena ; Cho, Sukhee ; Mungenast, Alison E. ; Muffat, Julien ; Mitalipova, Maisam ; Pluth, Michael D. ; Jui, Nathan T. ; Schul̈e, Birgitt ; Lippard, Stephen J. ; Tsai, Li Huei ; Krainc, Dimitri ; Buchwald, Stephen L. ; Jaenisch, Rudolf ; Lindquist, Susan. / Identification and rescue of α-synuclein toxicity in Parkinson patient-derived neurons. In: Science. 2013 ; Vol. 342, No. 6161. pp. 983-987.
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abstract = "The induced pluripotent stem (iPS) cell field holds promise for in vitro disease modeling. However, identifying innate cellular pathologies, particularly for age-related neurodegenerative diseases, has been challenging. Here, we exploited mutation correction of iPS cells and conserved proteotoxic mechanisms from yeast to humans to discover and reverse phenotypic responses to a-synuclein (asyn), a key protein involved in Parkinson 's disease (PD). We generated cortical neurons from iPS cells of patients harboring asyn mutations, who are at high risk of developing PD dementia. Genetic modifiers from unbiased screens in a yeast model of asyn toxicity led to identification of early pathogenic phenotypes in patient neurons. These included nitrosative stress, accumulation of endoplasmic reticulum (ER)-associated degradation substrates, and ER stress. A small molecule identified in a yeast screen (NAB2), and the ubiquitin ligase Nedd4 it affects, reversed pathologic phenotypes in these neurons.",
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Chung, CY, Khurana, V, Auluck, PK, Tardiff, DF, Mazzulli, JR, Soldner, F, Baru, V, Lou, Y, Freyzon, Y, Cho, S, Mungenast, AE, Muffat, J, Mitalipova, M, Pluth, MD, Jui, NT, Schul̈e, B, Lippard, SJ, Tsai, LH, Krainc, D, Buchwald, SL, Jaenisch, R & Lindquist, S 2013, 'Identification and rescue of α-synuclein toxicity in Parkinson patient-derived neurons', Science, vol. 342, no. 6161, pp. 983-987. https://doi.org/10.1126/science.1245296

Identification and rescue of α-synuclein toxicity in Parkinson patient-derived neurons. / Chung, Chee Yeun; Khurana, Vikram; Auluck, Pavan K.; Tardiff, Daniel F.; Mazzulli, Joseph R.; Soldner, Frank; Baru, Valeriya; Lou, Yali; Freyzon, Yelena; Cho, Sukhee; Mungenast, Alison E.; Muffat, Julien; Mitalipova, Maisam; Pluth, Michael D.; Jui, Nathan T.; Schul̈e, Birgitt; Lippard, Stephen J.; Tsai, Li Huei; Krainc, Dimitri; Buchwald, Stephen L.; Jaenisch, Rudolf; Lindquist, Susan.

In: Science, Vol. 342, No. 6161, 01.01.2013, p. 983-987.

Research output: Contribution to journalArticle

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AU - Chung, Chee Yeun

AU - Khurana, Vikram

AU - Auluck, Pavan K.

AU - Tardiff, Daniel F.

AU - Mazzulli, Joseph R.

AU - Soldner, Frank

AU - Baru, Valeriya

AU - Lou, Yali

AU - Freyzon, Yelena

AU - Cho, Sukhee

AU - Mungenast, Alison E.

AU - Muffat, Julien

AU - Mitalipova, Maisam

AU - Pluth, Michael D.

AU - Jui, Nathan T.

AU - Schul̈e, Birgitt

AU - Lippard, Stephen J.

AU - Tsai, Li Huei

AU - Krainc, Dimitri

AU - Buchwald, Stephen L.

AU - Jaenisch, Rudolf

AU - Lindquist, Susan

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