Molecular Features Underlying Neurodegeneration Identified through In Vitro Modeling of Genetically Diverse Parkinson's Disease Patients.
The fact that Parkinson's disease (PD) can arise from numerous genetic mutations suggests a unifying molecular pathology underlying the various genetic backgrounds. To address this hypothesis, we took an integrated approach utilizing in vitro disease modeling and comprehensive transcriptome profiling to advance our understanding of PD progression and the concordant downstream signaling pathways across divergent genetic predispositions. To model PD in vitro, we generated neurons harboring disease-causing mutations from patient-specific, induced pluripotent stem cells (iPSCs). We observed signs of degeneration in midbrain dopaminergic neurons, reflecting the cardinal feature of PD. Gene expression signatures of PD neurons provided molecular insights into disease phenotypes observed in vitro, including oxidative stress vulnerability and altered neuronal activity. Notably, PD neurons show that elevated RBFOX1, a gene previously linked to neurodevelopmental diseases, underlies a pattern of alternative RNA-processing associated with PD-specific phenotypes.
NUS Graduate School for Integrative Sciences and Engineering, Singapore 117456, Singapore; Stem Cell and Regenerative Biology Group, Genome Institute of Singapore, Singapore 138672, Singapore.
Lin
L
Lin
Computational and Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
Jonathan
J
Göke
Computational and Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
Engin
E
Cukuroglu
Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School, Singapore 169857, Singapore.
Mark R
MR
Dranias
Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School, Singapore 169857, Singapore.
Antonius M J
AM
VanDongen
Stem Cell and Regenerative Biology Group, Genome Institute of Singapore, Singapore 138672, Singapore; Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore. Electronic address: stantonl@gis.a-star.edu.sg.
Lawrence W
LW
Stanton
D017398:Alternative Splicing / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050259:Genes, Mitochondrial; D018740:Genetic Heterogeneity; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism; D008636:Mesencephalon / Q000473:pathology; D008954:Models, Biological; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D000072260:RNA Splicing Factors / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA; D059467:Transcriptome / Q000235:genetics; D051844:alpha-Synuclein / Q000378:metabolism
D009498:Neurotoxins; C455479:RBFOX1 protein, human; D000072260:RNA Splicing Factors; D051844:alpha-Synuclein