Abstract
Accumulation of α-synuclein (α-syn) into Lewy bodies (LBs) and mitochondrial abnormalities are the two cardinal pathobiological features of Parkinson’s disease (PD), which are associated with the loss of dopaminergic neurons. Although α-syn accumulates in many different cellular and mouse models, these models generally lack LB features. Here, we generated midbrain dopaminergic (mDA) neuronal cultures from induced pluripotent stem cells (iPSCs) derived from familial PD (fPD) patients and healthy controls. We show that mDA neuronal cultures from fPD patients with A53T mutation and α-syn gene (SNCA) triplication display pathological α-syn deposits, which spatially and morphologically resemble LBs. Importantly, we did not find any apparent accumulation of pathological α-syn in mDA neuronal culture derived from a healthy donor. Furthermore, we show that there are morphological abnormalities in the mitochondrial network in mDA neuronal cultures from fPD patients. Consequently, these cells were more susceptible to mitochondrial damage compared with healthy donor-derived mDA neuronal cultures. Our results indicate that the iPSC-derived mDA neuronal culture platform can be used to investigate the spatiotemporal appearance of LBs, as well as their composition, architecture, and relationship with mitochondrial abnormalities.
Highlights
Parkinson’s disease (PD) is pathologically characterized by the presence of α-synuclein (α-syn)-containing deposits in neuronal perikarya (Lewy bodies, LBs) and neuronal processes (Lewy neurites, LNs) and the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) [1]
We noted reduced immunostaining for the LIM homeobox transcription factor 1 alpha (LMX1A) in the midbrain progenitors derived from the A53T mutant line compared to that of the healthy line (Figure 2A)
A significant proportion of familial PD (fPD)-causing mutations reside in either the SNCA gene or genes associated with mitochondrial biology [17]
Summary
Parkinson’s disease (PD) is pathologically characterized by the presence of α-synuclein (α-syn)-containing deposits in neuronal perikarya (Lewy bodies, LBs) and neuronal processes (Lewy neurites, LNs) and the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) [1]. The predominant presence of α-syn aggregates in LBs and LNs along with disease-causing mutations in the SNCA gene substantiated the crucial role of α-syn aggregation in PD pathology. Α-syn accumulation in fPD-iPSC-derived DA neurons has been reported in multiple studies, the formation of LB-like structures in these cells has not been shown. We first investigated whether fPD-iPSC-derived DA neuronal cultures exhibit α-syn accumulations, with spatial and morphological resemblance to LBs. we tested whether fPD-iPSC-DA neuronal cultures manifest mitochondrial vulnerability. Using a floor-plate-based differentiation protocol [11], we generated DA neurons from a healthy individual and from fPD patient-derived iPSCs, carrying SNCA gene triplication and A53T mutation. FPD-iPSC-mDA neurons were associated with abnormal mitochondrial morphology and significant vulnerability to mitochondrial damage
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