ArticleProceedings of the National Academy of Sciences of the United States of America2017
Defective synaptic connectivity and axonal neuropathology in a human iPSC-based model of familial Parkinson's disease.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 92 papers, 1 of them a synthesis that pooled it.
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Who cites it
92 citing papers in PubMed, 1 synthesis or guideline pooled it, 156 citations in OpenAlex.
- Early Signs of Molecular Defects in iPSC-Derived Neural Stems Cells from Patients with Familial Parkinson's Disease.Biomolecules · 2022Pooled it
- A Live-Cell Imaging System for the Identification of Pro- and Anti-Aggregatory α-Synuclein Modulators.Molecular neurobiology · 2026Article
- α-Synuclein in Lewy Body Diseases: Progress, Remaining Challenges and Future Perspectives.Expert reviews in molecular medicine · 2026Review
- Optogenetic-induced α-synuclein accumulation reveals early synaptic dysfunction in experimental models of Parkinson's disease.NPJ Parkinson's disease · 2025Article
- Stem cells strike back: advancements in Alzheimer's and Parkinson's disease treatment and modeling efforts from 2019 to 2024.Journal of molecular medicine (Berlin, Germany) · 2025Review
- Dysregulated proteostasis in p.A53T-α-Synuclein astrocytes aggravates Lewy-like neuropathology in a Parkinson's disease iPSC model.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Dopamine and cortical neurons with different Parkinsonian mutations show variation in lysosomal and mitochondrial dysfunction.NPJ Parkinson's disease · 2025Article
- Loss of intracellular ATP affects axoplasmic viscosity and pathological protein aggregation in mammalian neurons.Science advances · 2025Article
- Current Development of iPSC-Based Modeling in Neurodegenerative Diseases.International journal of molecular sciences · 2025Review
- Stem Cell-Based Approaches in Parkinson's Disease Research.International journal of stem cells · 2025Review
- NPT100-18A rescues mitochondrial oxidative stress and neuronal degeneration in human iPSC-based Parkinson's model.BMC neuroscience · 2025Article
- Review
- Modeling early phenotypes of Parkinson's disease by age-induced midbrain-striatum assembloids.Communications biology · 2024Article
- Genetic Analysis of Neurite Outgrowth Inhibitor-Associated Genes in Parkinson's Disease: A Cross-Sectional Cohort Study.CNS neuroscience & therapeutics · 2024Article
- Human α-synuclein overexpression upregulates SKOR1 in a rat model of simulated nigrostriatal ageing.Aging cell · 2024Article
- Mutant α-synuclein causes death of human cortical neurons via ERK1/2 and JNK activation.Molecular brain · 2024Article
- Elevated parkinsonism pathological markers in dopaminergic neurons with developmental exposure to atrazine.The Science of the total environment · 2024Article
- Transcriptomic profiling of early synucleinopathy in rats induced with preformed fibrils.NPJ Parkinson's disease · 2024Article
- Inactivation of Tumor Suppressor CYLD Inhibits Fibroblast Reprogramming to Pluripotency.Cancers · 2023Article
- Recent Advances in High-Content Imaging and Analysis in iPSC-Based Modelling of Neurodegenerative Diseases.International journal of molecular sciences · 2023Review
32 more citing papers are in PubMed but not listed here.
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Authors and funding
18 authors at 7 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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 disease-relevant phenotypes, including protein aggregation, compromised neuritic outgrowth, and contorted or fragmented axons with swollen varicosities containing αSyn and Tau. The identified neuropathological features closely resembled those in brains of p.A53T patients. Small molecules targeting αSyn 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.
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