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

• DOI: 10.1016/j.celrep.2020.108263
• Publication Date: 2020-10-13T17:56:45Z
• Authors: Hugo J.R. Fernandes; Nikolaos Patikas; Stefanie Foskolou; Sarah F. Field; Jong-Eun Park; Meg L. Byrne; Andrew R. Bassett; Emmanouil Metzako...

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 study human iPSC-derived dopaminergic to elucidate gene expression dynamics in response cytotoxic and genetic stressors. We identify multiple neuronal subtypes with transcriptionally distinct profiles differential sensitivity stress, highlighting dopamine vitro validate this model by showing robust PD GWAS genes overlap postmortem adult substantia nigra neurons. Importantly, stress signatures are ameliorated using felodipine, an FDA-approved drug. Using isogenic SNCA-A53T mutants, find perturbations glycolysis, cholesterol metabolism, synaptic signaling, ubiquitin-proteasomal degradation. Overall, our reveals type-specific neurons, which will further understanding have implications for replacement therapies.