ArticleNPJ Parkinson's disease2022
Protein aggregation and calcium dysregulation are hallmarks of familial Parkinson's disease in midbrain dopaminergic neurons.
Article in NPJ Parkinson's disease, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 60 citations in OpenAlex.
- Parkinson's Disease: Pathophysiology, Treatment Strategies, Wellness Approaches, and Obstacles/Paths Forward.NeuroSci · 2026Review
- α-Synuclein pathology differentially alters T-type calcium currents in vulnerable and resilient substantia nigra dopaminergic subpopulations.bioRxiv : the preprint server for biology · 2026Article
- Modeling Parkinson's pathology in human iPSC dopaminergic neurons uncovers key mechanisms of Lewy body formation and heterogeneity.Science advances · 2026Article
- Targeting lysosomal pH restores mitochondrial quality control in GBA1-mutant Parkinson's disease.Translational neurodegeneration · 2026Article
- Cell-Type-Selective Cortical Pathology and Functional Deficits in Synucleinopathy.bioRxiv : the preprint server for biology · 2026Article
- The vicious cycle: unraveling the interplay between α-synuclein, mitochondrial dysfunction, and neuroinflammation in Parkinson's disease.Journal of neurology · 2026Review
- From retina to brain: retinal dysfunction and dopaminergic neurodegeneration inFrontiers in cell and developmental biology · 2026Article
- Optogenetic-induced α-synuclein accumulation reveals early synaptic dysfunction in experimental models of Parkinson's disease.NPJ Parkinson's disease · 2025Article
- Alpha-Synuclein Neurobiology in Parkinson's Disease: A Comprehensive Review of Its Role, Mechanisms, and Therapeutic Perspectives.Brain sciences · 2025Review
- BrainSTEM: A single-cell multiresolution fetal brain atlas reveals transcriptomic fidelity of human midbrain cultures.Science advances · 2025Article
- Parkinson's disease mutant Miro1 causes mitochondrial dysfunction and dopaminergic neuron loss.Brain : a journal of neurology · 2025Article
- Mitophagy's impacts on cancer and neurodegenerative diseases: implications for future therapies.Journal of hematology & oncology · 2025Review
- Conformational Switch in the Alpha-Synuclein C-Terminal Domain Directs Its Fibril Polymorphs.Chemistry (Weinheim an der Bergstrasse, Germany) · 2025Article
- Intact microdissection of stellate ganglia in a Parkinson's disease model reveals aggregation of mutant human α-synuclein in their cell bodies.Experimental physiology · 2025Article
- Caloric Restriction Mimetics as Priming Agents of Mesenchymal Stem Cells Secretome to Enhance Regenerative Responses to Parkinson's Disease.Molecules (Basel, Switzerland) · 2025Review
- Alpha-Synuclein Pathophysiology in Neurodegenerative Disorders: A Review Focusing on Molecular Mechanisms and Treatment Advances in Parkinson's Disease.Cellular and molecular neurobiology · 2025Review
- Modeling and correction of protein conformational disease in iPSC-derived neurons through personalized base editing.Molecular therapy. Nucleic acids · 2025Article
- Synaptic sabotage: How Tau and α-Synuclein undermine synaptic health.The Journal of cell biology · 2025Review
- Alpha-synuclein null mutation exacerbates the phenotype of a model of Menkes disease in female mice.Frontiers in neuroscience · 2025Article
- Review
Corrections and comments
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Authors and funding
26 authors at 8 institutions in 2 countries.
Funding
Abstract
Mutations in the SNCA gene cause autosomal dominant Parkinson's disease (PD), with loss of dopaminergic neurons in the substantia nigra, and aggregation of α-synuclein. The sequence of molecular events that proceed from an SNCA mutation during development, to end-stage pathology is unknown. Utilising human-induced pluripotent stem cells (hiPSCs), we resolved the temporal sequence of SNCA-induced pathophysiological events in order to discover early, and likely causative, events. Our small molecule-based protocol generates highly enriched midbrain dopaminergic (mDA) neurons: molecular identity was confirmed using single-cell RNA sequencing and proteomics, and functional identity was established through dopamine synthesis, and measures of electrophysiological activity. At the earliest stage of differentiation, prior to maturation to mDA neurons, we demonstrate the formation of small β-sheet-rich oligomeric aggregates, in SNCA-mutant cultures. Aggregation persists and progresses, ultimately resulting in the accumulation of phosphorylated α-synuclein aggregates. Impaired intracellular calcium signalling, increased basal calcium, and impairments in mitochondrial calcium handling occurred early at day 34-41 post differentiation. Once midbrain identity fully developed, at day 48-62 post differentiation, SNCA-mutant neurons exhibited mitochondrial dysfunction, oxidative stress, lysosomal swelling and increased autophagy. Ultimately these multiple cellular stresses lead to abnormal excitability, altered neuronal activity, and cell death. Our differentiation paradigm generates an efficient model for studying disease mechanisms in PD and highlights that protein misfolding to generate intraneuronal oligomers is one of the earliest critical events driving disease in human neurons, rather than a late-stage hallmark of the disease.
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Registered trials
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