ArticleThe FEBS journal2012
Role of α-synuclein penetration into the membrane in the mechanisms of oligomer pore formation.
Article in The FEBS journal, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 101 papers.
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Who cites it
101 citing papers in PubMed, 170 citations in OpenAlex.
- Single-molecule detection methods to study alpha-synuclein aggregation in postmortem Parkinson's disease brains.Cell reports methods · 2026Article
- Cardiolipin and mitochondrial membrane integrity in neurodegeneration: insights from α-synuclein-driven Parkinson's disease.Acta neuropathologica communications · 2025Review
- In situ exogenous alpha-synuclein aggregates inhibit murine ventricular voltage-gated inward sodium and outward potassium currents.Journal of Parkinson's disease · 2025Article
- Protein Recognition of Linear and Cyclic Peptides of Homologous Sequences Implicated in the Aggregation of α-Synuclein.The journal of physical chemistry. B · 2025Article
- Interaction Between α-Synuclein and DJ-1 in Parkinson's Disease.Brain sciences · 2025Review
- Gene delivery of SUMO1-derived peptide rescues neuronal degeneration and motor deficits in a mouse model of Parkinson's disease.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Increased burden of rare risk variants across gene expression networks predisposes to sporadic Parkinson's disease.Cell reports · 2025Article
- The interplay of iron, oxidative stress, and α-synuclein in Parkinson's disease progression.Molecular medicine (Cambridge, Mass.) · 2025Review
- Fc-Binding Cyclopeptide Induces Allostery from Fc to Fab: Revealed Through in Silico Structural Analysis to Anti-Phenobarbital Antibody.Foods (Basel, Switzerland) · 2025Article
- Preclinical assessment of a ganglioside-targeted therapy for Parkinson's disease with the first-in-class adaptive peptide AmyP53.Scientific reports · 2025Article
- TMEM16F regulates pathologic α-synuclein secretion and spread in cellular and mouse models of Parkinson's disease.Aging cell · 2025Article
- Associations Between Diabetes Mellitus and Neurodegenerative Diseases.International journal of molecular sciences · 2025Review
- α-Synuclein pathology as a target in neurodegenerative diseases.Nature reviews. Neurology · 2025Review
- The Contribution of Type 2 Diabetes to Parkinson's Disease Aetiology.International journal of molecular sciences · 2024Review
- Liquid-liquid phase separation and conformational strains ofFrontiers in molecular neuroscience · 2024Review
- Review
- Oligomeric and Fibrillar α-Synuclein Display Persistent Dynamics and Compressibility under Controlled Confinement.ACS chemical neuroscience · 2023Article
- Sex-dependent neuronal effects of α-synuclein reveal that GABAergic transmission is neuroprotective of sleep-controlling neurons.Cell & bioscience · 2023Article
- Review
- High-resolution structural information of membrane-bound α-synuclein provides insight into the MoA of the anti-Parkinson drug UCB0599.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
41 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Parkinson's disease (PD) and dementia with Lewy bodies are common disorders of the aging population and characterized by the progressive accumulation of α-synuclein (α-syn) in the central nervous system. Aggregation of α-syn into oligomers with a ring-like appearance has been proposed to play a role in toxicity. However, the molecular mechanisms and the potential sequence of events involved in the formation of pore-like structures are unclear. We utilized computer modeling and cell-based studies to investigate the process of oligomerization of wild-type and A53T mutant α-syn in membranes. The studies suggest that α-syn penetrates the membrane rapidly, changing its conformation from α-helical towards a coiled structure. This penetration facilitates the incorporation of additional α-syn monomers in the complex, and the subsequent displacement of phospholipids and the formation of oligomers in the membrane. This process occurred more rapidly, and with a more favorable energy of interaction, for mutant A53T compared with wild-type α-syn. After 4 ns of simulation of the protein-membrane model, α-syn had penetrated through two-thirds of the membrane. By 9 ns, the penetration of the annular α-syn oligomers can result in the formation of pore-like structures that fully perforate the lipid bilayer. Experimental incubation of recombinant α-syn in synthetic membranes resulted in the formation of similar pore-like complexes. Moreover, mutant (A53T) α-syn had a greater tendency to accumulate in neuronal membrane fractions in cell cultures, resulting in greater neuronal permeability, as demonstrated with the calcein efflux assay. These studies provide a sequential molecular explanation for the process of α-syn oligomerization in the membrane, and support the role of formation of pore-like structures in the pathogenesis of the neurodegenerative process in PD.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.