TY - JOUR
T1 - Molecular Features Underlying Neurodegeneration Identified through In Vitro Modeling of Genetically Diverse Parkinson's Disease Patients
AU - Lin, Lin
AU - Göke, Jonathan
AU - Cukuroglu, Engin
AU - Dranias, Mark R.
AU - VanDongen, Antonius M.J.
AU - Stanton, Lawrence W.
N1 - Publisher Copyright:
© 2016 The Author(s).
PY - 2016/6/14
Y1 - 2016/6/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84974659852&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2016.05.022
DO - 10.1016/j.celrep.2016.05.022
M3 - Article
C2 - 27264186
AN - SCOPUS:84974659852
SN - 2211-1247
VL - 15
SP - 2411
EP - 2426
JO - Cell Reports
JF - Cell Reports
IS - 11
ER -