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. 2020 Oct 13;33(2):108263.
doi: 10.1016/j.celrep.2020.108263.

Single-Cell Transcriptomics of Parkinson's Disease Human In Vitro Models Reveals Dopamine Neuron-Specific Stress Responses

Hugo J R Fernandes  1 , Nikolaos Patikas  2 , Stefanie Foskolou  1 , Sarah F Field  2 , Jong-Eun Park  3 , Meg L Byrne  4 , Andrew R Bassett  4 , Emmanouil Metzakopian  5
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Free article

Single-Cell Transcriptomics of Parkinson's Disease Human In Vitro Models Reveals Dopamine Neuron-Specific Stress Responses

Hugo J R Fernandes et al. Cell Rep. .
Free article

Abstract

The advent of induced pluripotent stem cell (iPSC)-derived neurons has revolutionized Parkinson's disease (PD) research, but single-cell transcriptomic analysis suggests unresolved cellular heterogeneity within these models. Here, we perform the largest single-cell transcriptomic study of human iPSC-derived dopaminergic neurons to elucidate gene expression dynamics in response to cytotoxic and genetic stressors. We identify multiple neuronal subtypes with transcriptionally distinct profiles and differential sensitivity to stress, highlighting cellular heterogeneity in dopamine in vitro models. We validate this disease model by showing robust expression of PD GWAS genes and overlap with postmortem adult substantia nigra neurons. Importantly, stress signatures are ameliorated using felodipine, an FDA-approved drug. Using isogenic SNCA-A53T mutants, we find perturbations in glycolysis, cholesterol metabolism, synaptic signaling, and ubiquitin-proteasomal degradation. Overall, our study reveals cell type-specific perturbations in human dopamine neurons, which will further our understanding of PD and have implications for cell replacement therapies.

Keywords: Cholesterol biosynthesis; Dopamine neurons; ER stress; Felodipine; Human iPSC; Oxidative stress; PD GWAS; Parkinson's disease; SNCA-A53T; Single-cell transcriptomics.

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Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

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