Wei Xiang, Germany
Universitätsklinikum Erlangen Department of Molecular NeurologyAuthor Of 1 Presentation
ALPHA-SYNUCLEIN PATHOLOGY RENDERS SELECTIVE VULNERABILITY TO MIDBRAIN NEURONS IN PARKINSON’S DISEASE
Abstract
Aims
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by protein inclusions mostly composed of aggregated α-synuclein (α-Syn) and by the progressive degeneration of midbrain dopaminergic neurons (mDANs). The relevance of α-Syn aggregation for the preferential loss of mDANs in PD pathology is not completely understood yet. We therefore aimed to elucidate the mechanisms of the brain region-specific neuronal vulnerability in PD.
Methods
We applied human induced pluripotent stem cells (iPSCs) from familial PD cases with a duplication (Dupl) of the α-Syn gene (SNCA) locus to model human PD. Human iPSCs from PD Dupl patients and a control individual were differentiated into mDANs and cortical projection neurons (CPNs) and assessed for neuronal cell death and α-Syn pathology degree.
Results
Elevated α-Syn pathology, as revealed by enhanced α-Syn insolubility and phosphorylation, was determined in PD-derived mDANs compared to PD CPNs. PD-derived mDANs exhibited higher levels of reactive oxygen species and protein nitration levels compared to 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. Inhibition of α-Syn oligomerization by a NPT100-18A compound rescued PD mDAN cell death. Our results reveal, for the first time, a higher α-Syn pathology, oxidative stress level, and neuronal death rate in human PD mDANs compared to PD CPNs from the same patient.
Conclusions
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.