Demonstration of brain region-specific neuronal vulnerability in human iPSC-based model of familial Parkinson's disease

Brazdis RM, Alecu JE, Marsch D, Dahms A, Simmnacher K, Lörentz S, Brendler A, Schneider Y, Marxreiter F, Roybon L, Winner B, Xiang W, Prots I (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Human Molecular Genetics Oxford University Press (OUP): Policy B - Oxford Open Option B

Book Volume: 29

Pages Range: 1180-1191

Journal Issue: 7

DOI: 10.1093/hmg/ddaa039

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterized by protein inclusions mostly composed of aggregated forms of α-synuclein (α-Syn) and by the progressive degeneration of midbrain dopaminergic neurons (mDANs), resulting in motor symptoms. While other brain regions also undergo pathologic changes in PD, the relevance of α-Syn aggregation for the preferential loss of mDANs in PD pathology is not completely understood yet. To elucidate the mechanisms of the brain region-specific neuronal vulnerability in PD, we modeled human PD using human-induced pluripotent stem cells (iPSCs) from familial PD cases with a duplication (Dupl) of the α-Syn gene (SNCA) locus. Human iPSCs from PD Dupl patients and a control individual were differentiated into mDANs and cortical projection neurons (CPNs). SNCA dosage increase did not influence the differentiation efficiency of mDANs and CPNs. However, elevated α-Syn pathology, as revealed by enhanced α-Syn insolubility and phosphorylation, was determined in PD-derived mDANs compared with PD CPNs. PD-derived mDANs exhibited higher levels of reactive oxygen species and protein nitration levels compared with CPNs, which might underlie elevated α-Syn pathology observed in mDANs. Finally, increased neuronal death was observed in PD-derived mDANs compared to PD CPNs and to control mDANs and CPNs. Our results reveal, for the first time, a higher α-Syn pathology, oxidative stress level, and neuronal death rate in human PD mDANs compared with PD CPNs from the same patient. The finding implies the contribution of pathogenic α-Syn, probably induced by oxidative stress, to selective vulnerability of substantia nigra dopaminergic neurons in human PD.

Authors with CRIS profile

Razvan Marius Brazdis Professur für Stammzell-Modelle seltener neuraler Erkrankungen Katrin Simmnacher Professur für Molekulare Neurologie Franz Marxreiter Department of Molecular Neurology Beate Winner Professur für Stammzell-Modelle seltener neuraler Erkrankungen Wei Xiang Department of Molecular Neurology Iryna Prots Professur für Stammzell-Modelle seltener neuraler Erkrankungen

Involved external institutions

Lund University / Lunds universitet SE Sweden (SE)

How to cite

APA:

Brazdis, R.M., Alecu, J.E., Marsch, D., Dahms, A., Simmnacher, K., Lörentz, S.,... Prots, I. (2020). Demonstration of brain region-specific neuronal vulnerability in human iPSC-based model of familial Parkinson's disease. Human Molecular Genetics, 29(7), 1180-1191. https://doi.org/10.1093/hmg/ddaa039

MLA:

Brazdis, Razvan Marius, et al. "Demonstration of brain region-specific neuronal vulnerability in human iPSC-based model of familial Parkinson's disease." Human Molecular Genetics 29.7 (2020): 1180-1191.

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