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Defective synaptic connectivity and axonal neuropathology in a human iPSC-based model of familial Parkinson's disease.

ABSTRACT: ?-Synuclein (?Syn) is the major gene linked to sporadic Parkinson's disease (PD), whereas the G209A (p.A53T) ?Syn mutation causes a familial form of PD characterized by early onset and a generally severe phenotype, including nonmotor manifestations. Here we generated de novo induced pluripotent stem cells (iPSCs) from patients harboring the p.A53T mutation and developed a robust model that captures PD pathogenic processes under basal conditions. iPSC-derived mutant neurons displayed novel disease-relevant phenotypes, including protein aggregation, compromised neuritic outgrowth, and contorted or fragmented axons with swollen varicosities containing ?Syn and Tau. The identified neuropathological features closely resembled those in brains of p.A53T patients. Small molecules targeting ?Syn reverted the degenerative phenotype under both basal and induced stress conditions, indicating a treatment strategy for PD and other synucleinopathies. Furthermore, mutant neurons showed disrupted synaptic connectivity and widespread transcriptional alterations in genes involved in synaptic signaling, a number of which have been previously linked to mental disorders, raising intriguing implications for potentially converging disease mechanisms.

SUBMITTER: Kouroupi G

PROVIDER: S-EPMC5422768 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Defective synaptic connectivity and axonal neuropathology in a human iPSC-based model of familial Parkinson's disease.

Kouroupi Georgia G Taoufik Era E Vlachos Ioannis S IS Tsioras Konstantinos K Antoniou Nasia N Papastefanaki Florentia F Chroni-Tzartou Dafni D Wrasidlo Wolfgang W Bohl Delphine D Stellas Dimitris D Stellas Dimitris D Politis Panagiotis K PK Vekrellis Kostas K Papadimitriou Dimitra D Stefanis Leonidas L Bregestovski Piotr P Hatzigeorgiou Artemis G AG Masliah Eliezer E Matsas Rebecca R

Proceedings of the National Academy of Sciences of the United States of America 20170417 18

α-Synuclein (αSyn) is the major gene linked to sporadic Parkinson's disease (PD), whereas the G209A (p.A53T) αSyn mutation causes a familial form of PD characterized by early onset and a generally severe phenotype, including nonmotor manifestations. Here we generated de novo induced pluripotent stem cells (iPSCs) from patients harboring the p.A53T mutation and developed a robust model that captures PD pathogenic processes under basal conditions. iPSC-derived mutant neurons displayed novel diseas ...[more]

PMID: 28416701

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Project description:Parkinson's disease (PD) is a neurodegenerative disease with unknown cause in the majority of patients, who are therefore considered "idiopathic" (IPD). PD predominantly affects dopaminergic neurons in the substantia nigra pars compacta (SNpc), yet the pathology is not limited to this cell type. Advancing age is considered the main risk factor for the development of IPD and greatly influences the function of microglia, the immune cells of the brain. With increasing age, microglia become dysfunctional and release pro-inflammatory factors into the extracellular space, which promote neuronal cell death. Accordingly, neuroinflammation has also been described as a feature of PD. So far, studies exploring inflammatory pathways in IPD patient samples have primarily focused on blood-derived immune cells or brain sections, but rarely investigated patient microglia in vitro. Accordingly, we decided to explore the contribution of microglia to IPD in a comparative manner using, both, iPSC-derived cultures and postmortem tissue. Our meta-analysis of published RNAseq datasets indicated an upregulation of IL10 and IL1B in nigral tissue from IPD patients. We observed increased expression levels of these cytokines in microglia compared to neurons using our single-cell midbrain atlas. Moreover, IL10 and IL1B were upregulated in IPD compared to control microglia. Next, to validate these findings in vitro, we generated IPD patient microglia from iPSCs using an established differentiation protocol. IPD microglia were more readily primed as indicated by elevated IL1B and IL10 gene expression and higher mRNA and protein levels of NLRP3 after LPS treatment. In addition, IPD microglia had higher phagocytic capacity under basal conditions-a phenotype that was further exacerbated upon stimulation with LPS, suggesting an aberrant microglial function. Our results demonstrate the significance of microglia as the key player in the neuroinflammation process in IPD. While our study highlights the importance of microglia-mediated inflammatory signaling in IPD, further investigations will be needed to explore particular disease mechanisms in these cells.

Dataset Information

Defective synaptic connectivity and axonal neuropathology in a human iPSC-based model of familial Parkinson's disease.

Publications

Defective synaptic connectivity and axonal neuropathology in a human iPSC-based model of familial Parkinson's disease.

Similar Datasets

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