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.
Highlights
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder affecting around 1% of the population aged over 65 years [1]
Due to the involvement of fibroblast growth factor (FGF) signaling pathways in the forebrain and midbrain patterning [22], cortical projection neurons (CPNs) were differentiated by using FGF2 as a modulator of proliferation and differentiation of the neural precursor cells (NPCs) [23], according to a previously published protocol [24]. midbrain dopaminergic neurons (mDANs) were generated by a combination of FGF8, known to promote dopaminergic differentiation [25], and small molecules to inhibit signaling pathways of transforming growth factor-β and bone morphogenetic protein [26]
The selective loss of midbrain tyrosine hydroxylase (TH)-positive neurons has been shown in post-mortem PD brains and in various animal PD models, preferential loss of mDANs in PD compared with other neuronal subtypes and the underlying mechanisms are less investigated, in particular in human disease models
Summary
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder affecting around 1% of the population aged over 65 years [1]. Emotional and cognitive disturbances, contributing to the non-motor symptoms of PD, are based on the dysregulation of cortical circuits, which are partly dependent on the midbrain dopamine system [4,5,6,7]. Another neuropathological hallmark of PD is the deposition of intracellular inclusions, mainly consisting of pathologically aggregated α-synuclein (α-Syn) in neuronal cell bodies and neurites, called Lewy bodies (LBs) and Lewy neurites (LNs), respectively [8]. PD patients carrying the SNCA locus duplication (Dupl) are characterized by the presence of a widespread Lewy pathology from the brainstem to the neocortex and neuronal loss in the SN [15]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call