@article{5c444b3d4c4a42a08a7d5011b4f9d299,
title = "Gene-corrected p.A30P SNCA patient-derived isogenic neurons rescue neuronal branching and function",
abstract = "Parkinson{\textquoteright}s disease (PD) is characterised by the degeneration of A9 dopaminergic neurons and the pathological accumulation of alpha-synuclein. The p.A30P SNCA mutation generates the pathogenic form of the alpha-synuclein protein causing an autosomal-dominant form of PD. There are limited studies assessing pathogenic SNCA mutations in patient-derived isogenic cell models. Here we provide a functional assessment of dopaminergic neurons derived from a patient harbouring the p.A30P SNCA mutation. Using two clonal gene-corrected isogenic cell lines we identified image-based phenotypes showing impaired neuritic processes. The pathological neurons displayed impaired neuronal activity, reduced mitochondrial respiration, an energy deficit, vulnerability to rotenone, and transcriptional alterations in lipid metabolism. Our data describes for the first time the mutation-only effect of the p.A30P SNCA mutation on neuronal function, supporting the use of isogenic cell lines in identifying image-based pathological phenotypes that can serve as an entry point for future disease-modifying compound screenings and drug discovery strategies.",
author = "Barbuti, {Peter A.} and Jochen Ohnmacht and Santos, {Bruno F.R.} and Antony, {Paul M.} and Fran{\c c}ois Massart and G{\'e}rald Cruciani and Dording, {Claire M.} and Lukas Pavelka and Nicolas Casadei and Kwon, {Yong Jun} and Rejko Kr{\"u}ger",
note = "Funding Information: This research was funded by grants from the Fond National de Recherche within the PEARL programme (FNR/ P13/6682797), the INTER programme (INTER/LEIR/18/12719318) and the National Centre for Excellence in Research on Parkinson{\textquoteright}s disease (NCER-PD) programme and by the European Union{\textquoteright}s Horizon 2020 research and innovation programme under Grant Agreement No 692320 (WIDESPREAD; CENTRE-PD). NGS sequencing methods were performed with the support of the DFG-funded NGS Competence Center T{\"u}bingen Germany (INST 37/1049-1). Thanks to Aur{\'e}lien Ginolhac who developed and maintains the RNA-seq snakemake pipe-line at the DLSM, University Luxembourg. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = nov,
day = "9",
doi = "10.1038/s41598-021-01505-x",
language = "English",
volume = "11",
pages = "21946",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",
}