ArticleBiochemistry2015
Purification of α-synuclein from human brain reveals an instability of endogenous multimers as the protein approaches purity.
Article in Biochemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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47 citing papers in PubMed, 73 citations in OpenAlex.
- Incense Aerosol-Induced Neurotoxicity Disrupts α-Synuclein Homeostasis in a Cellular Parkinson's Disease Model, Distinct from Cigarette Aerosols.Chemical research in toxicology · 2026Article
- Stearoyl-CoA desaturase inhibition normalizes brain lipid saturation, α-synuclein homeostasis, and motor function in mutant Gba1-Parkinson mice.JCI insight · 2025Article
- Interaction between α-Synuclein and Bioactive Lipids: Neurodegeneration, Disease Biomarkers and Emerging Therapies.Metabolites · 2024Review
- The Parkinson-Associated Toxin Paraquat Shifts Physiological α-Synuclein Tetramers toward Monomers That Can Be Calpain-Truncated and Form Oligomers.The American journal of pathology · 2023Article
- Single point mutations at the S129 residue of α-synuclein and their effect on structure, aggregation, and neurotoxicity.Frontiers in chemistry · 2023Article
- Monitoring α-synuclein aggregation.Neurobiology of disease · 2023Review
- Neuronal Oxidative Stress Promotes α-Synuclein Aggregation In Vivo.Antioxidants (Basel, Switzerland) · 2022Article
- Opportunities and challenges of alpha-synuclein as a potential biomarker for Parkinson's disease and other synucleinopathies.NPJ Parkinson's disease · 2022Review
- Identification of allosteric fingerprints of alpha-synuclein aggregates in matrix metalloprotease-1 and substrate-specific virtual screening with single molecule insights.Scientific reports · 2022Article
- Brain region-specific susceptibility of Lewy body pathology in synucleinopathies is governed by α-synuclein conformations.Acta neuropathologica · 2022Article
- How important is the N-terminal acetylation of alpha-synuclein for its function and aggregation into amyloids?Frontiers in neuroscience · 2022Review
- Examining the Toxicity of α-Synuclein in Neurodegenerative Disorders.Life (Basel, Switzerland) · 2021Review
- Wild-type GBA1 increases the α-synuclein tetramer-monomer ratio, reduces lipid-rich aggregates, and attenuates motor and cognitive deficits in mice.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Potent inhibitors of toxic alpha-synuclein identified via cellular time-resolved FRET biosensors.NPJ Parkinson's disease · 2021Article
- Sigma-2 receptor antagonists rescue neuronal dysfunction induced by Parkinson's patient brain-derived α-synuclein.Journal of neuroscience research · 2021Article
- Effects of Excess Brain-Derived Human α-Synuclein on Synaptic Vesicle Trafficking.Frontiers in neuroscience · 2021Article
- Similarity of the non-amyloid-β component and C-terminal tail of monomeric and tetrameric alpha-synuclein with 14-3-3 sigma.Computational and structural biotechnology journal · 2021Article
- A method of purifying alpha-synuclein inHeliyon · 2021Article
- Iron-responsive-like elements and neurodegenerative ferroptosis.Learning & memory (Cold Spring Harbor, N.Y.) · 2020Review
- Navigating the dynamic landscape of alpha-synuclein morphology: a review of the physiologically relevant tetrameric conformation.Neural regeneration research · 2020Review
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5 authors at 2 institutions in 1 country.
Funding
Abstract
Despite two decades of research, the structure-function relationships of endogenous, physiological forms of α-synuclein (αSyn) are not well understood. Most in vitro studies of this Parkinson's disease-related protein have focused on recombinant αSyn that is unfolded and monomeric, assuming that this represents its state in the normal human brain. Recently, we have provided evidence that αSyn exists in considerable part in neurons, erythrocytes, and other cells as a metastable multimer that principally sizes as a tetramer. In contrast to recombinant αSyn, physiological tetramers purified from human erythrocytes have substantial α-helical content and resist pathological aggregation into β-sheet rich fibers. Here, we report the first method to fully purify soluble αSyn from the most relevant source, human brain. We describe protocols that purify αSyn to homogeneity from nondiseased human cortex using ammonium sulfate precipitation, gel filtration, and ion exchange, hydrophobic interaction, and affinity chromatographies. Cross-linking of the starting material and the partially purified chromatographic fractions revealed abundant αSyn multimers, including apparent tetramers, but these were destabilized in large part to monomers during the final purification step. The method also fully purified the homologue β-synuclein, with a similar outcome. Circular dichroism spectroscopy showed that purified, brain-derived αSyn can display more helical content than the recombinant protein, but this result varied. Collectively, our data suggest that purifying αSyn to homogeneity destabilizes native, α-helix-rich multimers that exist in intact and partially purified brain samples. This finding suggests existence of a stabilizing cofactor (e.g., a small lipid) present inside neurons that is lost during final purification.
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