Regulation of exocytosis and mitochondrial relocalization by Alpha-synuclein in a mammalian cell model

We characterized phenotypes in RBL-2H3 mast cells transfected with human alpha synuclein (a-syn) using stimulated exocytosis of recycling endosomes as a proxy for similar activities of synaptic vesicles in neurons. We found that low expression of a-syn inhibits stimulated exocytosis and that higher expression causes slight enhancement. NMR measurements of membrane interactions correlate with these functional effects: they are eliminated differentially by mutants that perturb helical structure in the helix 1 (A30P) or NAC/helix-2 (V70P) regions of membrane-bound a-syn, but not by other PD-associated mutants or C-terminal truncation. We further found that a-syn (but not A30P or V70P mutants) associates weakly with mitochondria, but this association increases markedly under conditions of cellular stress. These results highlight the importance of specific structural features of a-syn in regulating vesicle release, and point to a potential role for a-syn in perturbing mitochondrial function under pathological conditions.

• Publication year

  2018

• Venue

  npj Parkinson's Disease

• Publication date

  2018-12-10

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1038/s41531-019-0084-6PMID 31263746PMCID 6597712
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Synaptojanin and Endophilin Mediate Neck Formation during Ultrafast Endocytosis.

  2018cited by this paper
• A liquid phase of synapsin and lipid vesicles

  2018cited by this paper
• Cell Biology and Pathophysiology of α-Synuclein.

  2018cited by this paper
• Impacts of increased α-synuclein on clathrin-mediated endocytosis at synapses: implications for neurodegenerative diseases

  2018cited by this paper
• Lewy Body Disease: Clinical and Pathological “Overlap Syndrome” Between Synucleinopathies (Parkinson Disease) and Tauopathies (Alzheimer Disease)

  2018cited by this paper
• C-terminal calcium binding of α-synuclein modulates synaptic vesicle interaction

  2018cited by this paper
• Cytosolic Proteostasis via Importing of Misfolded Proteins into Mitochondria

  2017cited by this paper
• α-Synuclein Dimers Impair Vesicle Fission during Clathrin-Mediated Synaptic Vesicle Recycling

  2017cited by this paper
• Synucleins Have Multiple Effects on Presynaptic Architecture.

  2017cited by this paper
• The FcεRI signaling cascade and integrin trafficking converge at patterned ligand surfaces

  2017cited by this paper
• α-Synuclein - Regulator of Exocytosis, Endocytosis, or Both?

  2017cited by this paper
• Mitochondrial dynamics in Parkinson's disease: a role for α-synuclein?

  2017cited by this paper
• α-Synuclein Promotes Dilation of the Exocytotic Fusion Pore

  2017cited by this paper
• Semisynthetic and in Vitro Phosphorylation of Alpha-Synuclein at Y39 Promotes Functional Partly Helical Membrane-Bound States Resembling Those Induced by PD Mutations.

  2016cited by this paper
• α-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson’s disease

  2016cited by this paper
• Rab11 Regulates the Mast Cell Exocytic Response

  2016influential reference
• α-Synuclein Mutation Inhibits Endocytosis at Mammalian Central Nerve Terminals

  2016cited by this paper
• Phenotypic spectrum of alpha-synuclein mutations: New insights from patients and cellular models.

  2016cited by this paper
• Structural basis of synaptic vesicle assembly promoted by α-synuclein

  2016cited by this paper
• Structural disorder of monomeric α-synuclein persists in mammalian cells

  2016cited by this paper
• Biophysics of α-synuclein induced membrane remodelling.

  2015cited by this paper
• The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson's disease.

  2015influential reference
• Definition of a Molecular Pathway Mediating α-Synuclein Neurotoxicity

  2015cited by this paper
• Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease

  2014influential reference
• Dysregulation of protein trafficking in neurodegeneration

  2014cited by this paper
• Acute increase of α-synuclein inhibits synaptic vesicle recycling evoked during intense stimulation

  2014cited by this paper
• Clathrin regenerates synaptic vesicles from endosomes

  2014cited by this paper
• α-Synuclein Is Localized to Mitochondria-Associated ER Membranes

  2014cited by this paper
• Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins

  2014cited by this paper
• Alpha-Synuclein Function and Dysfunction on Cellular Membranes

  2014cited by this paper
• α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner.

  2014cited by this paper
• Alpha‐Synuclein Binds to the Inner Membrane of Mitochondria in an α‐Helical Conformation

  2014cited by this paper
• Activation of Cdc42 is necessary for sustained oscillations of Ca2+ and PIP2 stimulated by antigen in RBL mast cells

  2014cited by this paper
• Synucleins Regulate the Kinetics of Synaptic Vesicle Endocytosis

  2014cited by this paper
• Reduced glucocerebrosidase is associated with increased α-synuclein in sporadic Parkinson's disease.

  2014cited by this paper
• Mast cell secretory granules: armed for battle

  2014cited by this paper
• α-Synuclein assembles into higher-order multimers upon membrane binding to promote SNARE complex formation

  2014cited by this paper
• Parkinson's disease dementia: convergence of α-synuclein, tau and amyloid-β pathologies

  2013cited by this paper
• In Vivo Cross-linking Reveals Principally Oligomeric Forms of α-Synuclein and β-Synuclein in Neurons and Non-neural Cells*

  2013cited by this paper
• α‐Synuclein as an intrinsically disordered monomer – fact or artefact?

  2013cited by this paper
• Synaptic vesicle endocytosis.

  2012cited by this paper
• Nigrostriatal overabundance of α-synuclein leads to decreased vesicle density and deficits in dopamine release that correlate with reduced motor activity

  2012cited by this paper
• Roles for Ca2+ Mobilization and Its Regulation in Mast Cell Functions

  2012cited by this paper
• Impaired neurotransmission caused by overexpression of α-synuclein in nigral dopamine neurons

  2012cited by this paper
• Synaptic vesicle pools and dynamics.

  2012influential reference
• Systematic Mutagenesis of α-Synuclein Reveals Distinct Sequence Requirements for Physiological and Pathological Activities

  2012cited by this paper
• Biophysics of α-synuclein membrane interactions.

  2012cited by this paper
• α-Synuclein Inhibits Intersynaptic Vesicle Mobility and Maintains Recycling-Pool Homeostasis

  2012cited by this paper
• Folding and misfolding of alpha-synuclein on membranes.

  2012influential reference
• Calcium control of neurotransmitter release.

  2012cited by this paper
• Sequence correction of random coil chemical shifts: correlation between neighbor correction factors and changes in the Ramachandran distribution

  2011cited by this paper
• Direct Membrane Association Drives Mitochondrial Fission by the Parkinson Disease-associated Protein α-Synuclein*♦

  2011cited by this paper
• Random coil chemical shift for intrinsically disordered proteins: effects of temperature and pH

  2011cited by this paper
• Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis.

  2010cited by this paper
• The Lipid-binding Domain of Wild Type and Mutant α-Synuclein

  2010cited by this paper
• α-Synuclein Promotes SNARE-Complex Assembly in Vivo and in Vitro

  2010cited by this paper
• α-Synuclein Delays Endoplasmic Reticulum (ER)-to-Golgi Transport in Mammalian Cells by Antagonizing ER/Golgi SNAREs

  2010cited by this paper
• Effects of curvature and composition on α-synuclein binding to lipid vesicles.

  2010cited by this paper
• Membrane Curvature Induction and Tubulation Are Common Features of Synucleins and Apolipoproteins*

  2010cited by this paper
• Increased Expression of a-Synuclein Reduces Neurotransmitter Release by Inhibiting Synaptic Vesicle Reclustering after Endocytosis

  2010influential reference
• Alpha-synuclein binds large unilamellar vesicles as an extended helix.

  2009cited by this paper
• Interplay of α-synuclein binding and conformational switching probed by single-molecule fluorescence

  2009cited by this paper
• The influence of vesicle size and composition on alpha-synuclein structure and stability.

  2009cited by this paper
• Pathways and mechanisms of endocytic recycling

  2009cited by this paper
• Differential Phospholipid Binding of α-Synuclein Variants Implicated in Parkinson’s Disease Revealed by Solution NMR Spectroscopy†

  2009cited by this paper
• The Parkinson's disease protein α-synuclein disrupts cellular Rab homeostasis

  2008cited by this paper
• Mitochondrial localization of alpha-synuclein protein in alpha-synuclein overexpressing cells.

  2008cited by this paper
• Optical Reporters for the Conformation of α-Synuclein Reveal a Specific Interaction with Mitochondria

  2008cited by this paper
• Structure of membrane-bound α-synuclein from site-directed spin labeling and computational refinement

  2008cited by this paper
• Semi-quantitative analysis of alpha-synuclein in subcellular pools of rat brain neurons: an immunogold electron microscopic study using a C-terminal specific monoclonal antibody.

  2008cited by this paper
• Parkin is recruited selectively to impaired mitochondria and promotes their autophagy

  2008cited by this paper
• Membrane-bound alpha-synuclein forms an extended helix: long-distance pulsed ESR measurements using vesicles, bicelles, and rodlike micelles.

  2008cited by this paper
• The Parkinson's disease protein alpha-synuclein disrupts cellular Rab homeostasis.

  2008cited by this paper
• Mitochondrial translocation of alpha-synuclein is promoted by intracellular acidification.

  2008cited by this paper
• Protein Folding and Aggregation in in vitro Models of Parkinson's Disease: Structure and Function of α-Synuclein

  2008cited by this paper
• Localization of &agr;-synuclein to mitochondria within midbrain of mice

  2007cited by this paper
• Multiple hit hypotheses for dopamine neuron loss in Parkinson's disease.

  2007cited by this paper
• Levels of alpha‐synuclein mRNA in sporadic Parkinson disease patients

  2006cited by this paper
• Faculty Opinions recommendation of Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models.

  2006cited by this paper
• α-Synuclein Blocks ER-Golgi Traffic and Rab1 Rescues Neuron Loss in Parkinson's Models

  2006cited by this paper
• The parkinson's complex: Parkinsonism is just the tip of the iceberg

  2006cited by this paper
• α-Synuclein Overexpression in PC12 and Chromaffin Cells Impairs Catecholamine Release by Interfering with a Late Step in Exocytosis

  2006cited by this paper
• Transmembrane Sequences Are Determinants of Immunoreceptor Signaling 1

  2005cited by this paper
• Structure and Dynamics of Micelle-bound Human α-Synuclein*

  2005cited by this paper
• Transmembrane Sequences Are Determinants of Immunoreceptor Signaling

  2005cited by this paper
• The CCPN data model for NMR spectroscopy: Development of a software pipeline

  2005cited by this paper
• Effects of Parkinson's disease-linked mutations on the structure of lipid-associated alpha-synuclein.

  2004cited by this paper
• Structural Basis of Mitochondrial Tethering by Mitofusin Complexes

  2004cited by this paper
• Effects of Parkinson's disease-linked mutations on the structure of lipid-associated α-Synuclein

  2004cited by this paper
• A structural and functional role for 11-mer repeats in alpha-synuclein and other exchangeable lipid binding proteins.

  2003cited by this paper
• Antigen‐Stimulated Trafficking from the Recycling Compartment to the Plasma Membrane in RBL Mast Cells

  2003cited by this paper
• Lipid Droplet Binding and Oligomerization Properties of the Parkinson's Disease Protein α-Synuclein*

  2002cited by this paper
• Conformational properties of alpha-synuclein in its free and lipid-associated states.

  2001cited by this paper
• Acceleration of oligomerization, not fibrillization, is a shared property of both alpha-synuclein mutations linked to early-onset Parkinson's disease: implications for pathogenesis and therapy.

  2000cited by this paper
• Rat basophilic leukemia cells express syntaxin-3 and VAMP-7 in granule membranes.

  2000cited by this paper
• Heteronuclear multidimensional NMR experiments for the structure determination of proteins in solution employing pulsed field gradients

  1999cited by this paper
• Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are alpha-synucleinopathies.

  1999cited by this paper
• Binding of α-Synuclein to Brain Vesicles Is Abolished by Familial Parkinson’s Disease Mutation*

  1998cited by this paper
• Stabilization of α-Synuclein Secondary Structure upon Binding to Synthetic Membranes*

  1998cited by this paper
• In vivo zippering of inner and outer mitochondrial membranes by a stable translocation intermediate.

  1997cited by this paper

• How Are Synaptic Vesicle Exocytosis and Endocytosis Affected in Parkinson Disease?

  2026cites this paper
• Alpha-synuclein modulates the positioning of endolysosomes in melanoma cells

  2025cites this paper
• Plasma acellular transcriptome contains Parkinson’s disease signatures that can inform clinical diagnosis

  2024cites this paper
• Pulsed electric field induces exocytosis and overexpression of MAGE antigens in melanoma

  2024cites this paper
• α-Synuclein and biological membranes: the danger of loving too much

  2023cites this paper
• Exploring Intra- and Inter-Regional Interactions in the IDP α-Synuclein Using smFRET and MD Simulations

  2023cites this paper
• Quantitative Seed Amplification Assay: A Proof-of-Principle Study

  2023cites this paper
• Alpha Synuclein Modulates Mitochondrial Ca2+ Uptake from ER During Cell Stimulation and Under Stress Conditions

  2023cites this paper
• Docosahexaenoic acid promotes vesicle clustering mediated by alpha-Synuclein via electrostatic interaction

  2023cites this paper
• Alpha synuclein modulates mitochondrial Ca2+ uptake from ER during cell stimulation and under stress conditions

  2023cites this paper
• The Effects of Lipids on α-Synuclein Aggregation In Vitro

  2023cites this paper
• Plasticity of Membrane Binding by the Central Region of α-Synuclein

  2022influential citation
• Molecular and functional interactions of alpha-synuclein with Rab3a

  2022cites this paper
• The Role of Membrane Affinity and Binding Modes in Alpha-Synuclein Regulation of Vesicle Release and Trafficking

  2022influential citation
• The localization of alpha-synuclein in the endocytic pathway.

  2021cites this paper
• Parkinson's disease

  2021cites this paper
• Dietary nanoparticles compromise epithelial integrity and enhance translocation and antigenicity of milk proteins: An in vitro investigation.

  2021cites this paper
• α-Synuclein kinetically regulates the nascent fusion pore dynamics

  2021cites this paper
• Microplatforms as a model for neurological conditions

  2021cites this paper
• Alpha-Synuclein: Biomarker for Parkinson’s Disease, It’s Estimation Methods, and Targeted Medicinal Therapies

  2021cites this paper
• Interactions between SARS-CoV-2 N-Protein and α-Synuclein Accelerate Amyloid Formation

  2021cites this paper
• The docking of synaptic vesicles on the presynaptic membrane induced by α-synuclein is modulated by lipid composition

  2021cites this paper
• Megadalton-sized Dityrosine Aggregates of α-Synuclein Retain High Degrees of Structural Disorder and Internal Dynamics

  2020cites this paper
• Membrane interactions of intrinsically disordered proteins: The example of alpha-synuclein.

  2019cites this paper
• Intrinsically disordered proteins in synaptic vesicle trafficking and release

  2019cites this paper
• Dynamic instability of clathrin assembly provides proofreading control for endocytosis

  2019cites this paper
• Impacts of increased α-synuclein on clathrin-mediated endocytosis at synapses: implications for neurodegenerative diseases

  2018cites this paper