ArticleActa neuropathologica communications2021
In Parkinson's patient-derived dopamine neurons, the triplication of α-synuclein locus induces distinctive firing pattern by impeding D2 receptor autoinhibition.
Article in Acta neuropathologica communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 35 citations in OpenAlex.
- Immune-mediated excitotoxicity in brain disorders.Nature reviews. Immunology · 2026Review
- Synaptojanin1 regulates synaptic dopamine release and axonal integrity via retromer-dependent endosomal sorting.Research square · 2026Article
- From Neuroadaptation to Neuroprogression: Rethinking Chronic Cocaine Exposure Through a Model of Cocaine-Related Cerebropathy.Journal of clinical medicine · 2026Article
- Enteric glia, neuropeptides, and Parkinson's: impacts of calcitonin gene-related peptide on gut alpha synuclein.American journal of physiology. Gastrointestinal and liver physiology · 2026Article
- Article
- Chronic hyperactivation of midbrain dopamine neurons causes preferential dopamine neuron degeneration.eLife · 2025Article
- Parkinson's paradox: alpha-synuclein's selective strike on SNc dopamine neurons over VTA.NPJ Parkinson's disease · 2025Article
- Sex Specific Effects of Environmental Toxin-Derived Alpha Synuclein on Enteric Neuronal-Epithelial Interactions.Neurogastroenterology and motility · 2025Article
- Stem Cell-Based Approaches in Parkinson's Disease Research.International journal of stem cells · 2025Review
- Alpha-Synuclein Gene Alterations Modulate Tyrosine Hydroxylase in Human iPSC-Derived Neurons in a Parkinson's Disease Animal Model.Life (Basel, Switzerland) · 2024Article
- A stem cell-based assay platform demonstrates alpha-synuclein dependent synaptic dysfunction in patient-derived cortical neurons.NPJ Parkinson's disease · 2024Article
- Dopamine Signaling in Substantia Nigra and Its Impact on Locomotor Function-Not a New Concept, but Neglected Reality.International journal of molecular sciences · 2024Review
- Elevated parkinsonism pathological markers in dopaminergic neurons with developmental exposure to atrazine.The Science of the total environment · 2024Article
- Advances in understanding the function of alpha-synuclein: implications for Parkinson's disease.Brain : a journal of neurology · 2023Review
- Impaired dopamine release in Parkinson's disease.Brain : a journal of neurology · 2023Review
- Unraveling the Complex Interplay between Alpha-Synuclein and Epigenetic Modification.International journal of molecular sciences · 2023Review
- Alpha-synuclein oligomers alter the spontaneous firing discharge of cultured midbrain neurons.Frontiers in cellular neuroscience · 2023Article
- The complex role of inflammation and gliotransmitters in Parkinson's disease.Neurobiology of disease · 2023Review
- Synucleinopathy in Amyotrophic Lateral Sclerosis: A Potential Avenue for Antisense Therapeutics?International journal of molecular sciences · 2022Review
- Induced pluripotent stem cells: a tool for modeling Parkinson's disease.Trends in neurosciences · 2022Review
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Pathophysiological changes in dopamine neurons precede their demise and contribute to the early phases of Parkinson's disease (PD). Intracellular pathological inclusions of the protein α-synuclein within dopaminergic neurons are a cardinal feature of PD, but the mechanisms by which α-synuclein contributes to dopaminergic neuron vulnerability remain unknown. The inaccessibility to diseased tissue has been a limitation in studying progression of pathophysiology prior to degeneration of dopamine neurons. To address these issues, we differentiated induced pluripotent stem cells (iPSCs) from a PD patient carrying the α-synuclein triplication mutation (AST) and an unaffected first-degree relative (NAS) into dopaminergic neurons. In human-like dopamine neurons α-synuclein overexpression reduced the functional availability of D2 receptors, resulting in a stark dysregulation in firing activity, dopamine release, and neuronal morphology. We back-translated these findings into primary mouse neurons overexpressing α-synuclein and found a similar phenotype, supporting the causal role for α-synuclein. Importantly, application of D2 receptor agonist, quinpirole, restored the altered firing activity of AST-derived dopaminergic neurons to normal levels. These results provide novel insights into the pre-degenerative pathophysiological neuro-phenotype induced by α-synuclein overexpression and introduce a potential mechanism for the long-established clinical efficacy of D2 receptor agonists in the treatment of PD.
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Registered trials
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