Gene expression-based screen for Parkinson's disease identifies GW8510 as a neuroprotective agent

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Authors
Wimalasena, Nivanthika K.
Le, Viet Q.
Wimalasena, Kandatege
Schreiber, Stuart L.
Karmacharya, Rakesh
Advisors
Issue Date
2016-07
Type
Article
Keywords
GW8510 , Parkinson's disease , Neuroprotection , Induced pluripotent stem cells , iPSC , Neural progenitor cells
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Citation
Gene Expression-Based Screen for Parkinson’s Disease Identifies GW8510 as a Neuroprotective Agent Nivanthika K. Wimalasena, Viet Q. Le, Kandatege Wimalasena, Stuart L. Schreiber, and Rakesh Karmacharya ACS Chemical Neuroscience 2016 7 (7), 857-863
Abstract

We carried out a gene expression-based in silico screen in order to identify small molecules with gene-expression profiles that are anticorrelated with a gene-expression profile for Parkinson's disease (PD). We identified the cyclin-dependent kinase 2/5 (CDK2/5) inhibitor GW8510 as our most significant hit and characterized its effects in rodent MN9D cells and in human neuronal cells derived from induced pluripotent stem cells. GW8510 demonstrated neuroprotective ability in MN9D cells in the presence of 1-methyl-4-phenylpyridium (MPP+), a widely used neurotoxin model for Parkinson's disease. In order to delineate the nature and extent of GW8510's neuroprotective properties, we studied GW8510 in human neuronal cells in the context of various mechanisms of cellular stress. We found that GW8510 was protective against small-molecule mitochondrial and endoplasmic reticulum stressors. Our findings illustrate an approach to using small-molecule gene expression libraries to identify compounds with therapeutic potential in human diseases.

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Publisher
American Chemical Society
Journal
Book Title
Series
ACS Chemical Neuroscience;v.7:no.7
PubMed ID
DOI
ISSN
1948-7193
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