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

Ramezani, Meraj; Wilkes, Marcus; Das, Tapojyoti; Holowka, David; Eliezer, David; Baird, Barbara

doi:10.1038/s41531-019-0084-6

Cited by 24 publications

(70 citation statements)

References 104 publications

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“…Upon the binding of SVs, αS has a tendency to promote their clustering [12][13][14]17 , a process that has been associated with the maintenance of SV pools at the synaptic termini 11,[18][19][20] . Additionally, αS has been shown to influence the regulation of the vesicle trafficking from the endoplasmic reticulum (ER) to the Golgi 13,20 , and to localise at mitochondrial membranes, where it has been proposed to mitigate the effects of oxidative stress [21][22][23][24] . All these putative functions by αS require its binding to biological membranes 25,26 , a central interaction that defines the relevant biological form of αS in vivo 27 and influences the kinetics of its aggregation 11,28,29 , as well as the toxicity of its aggregates 1,30,31 .…”

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confidence: 99%

The docking of synaptic vesicles on the presynaptic membrane induced by α-synuclein is modulated by lipid composition

et al. 2021

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Abstractα-Synuclein (αS) is a presynaptic disordered protein whose aberrant aggregation is associated with Parkinson’s disease. The functional role of αS is still debated, although it has been involved in the regulation of neurotransmitter release via the interaction with synaptic vesicles (SVs). We report here a detailed characterisation of the conformational properties of αS bound to the inner and outer leaflets of the presynaptic plasma membrane (PM), using small unilamellar vesicles. Our results suggest that αS preferentially binds the inner PM leaflet. On the basis of these studies we characterise in vitro a mechanism by which αS stabilises, in a concentration-dependent manner, the docking of SVs on the PM by establishing a dynamic link between the two membranes. The study then provides evidence that changes in the lipid composition of the PM, typically associated with neurodegenerative diseases, alter the modes of binding of αS, specifically in a segment of the sequence overlapping with the non-amyloid component region. Taken together, these results reveal how lipid composition modulates the interaction of αS with the PM and underlie its functional and pathological behaviours in vitro.

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confidence: 99%

The docking of synaptic vesicles on the presynaptic membrane induced by α-synuclein is modulated by lipid composition

et al. 2021

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“…apoptosis (12). Recent findings substantiate this notion by revealing direct interactions between aSyn and mitochondrial membranes and lipids (13,14), aSyn-induced organelle toxicity (15, 16,Mahul-Mellier, 2020 #93), stress-related re-localization of aSyn to mitochondria (17,18) and pathological colocalization with mitochondria (and other non-proteinaceous structures) in brain-derived LB inclusions (5) and cellular models of LB formation and maturation (4). In addition, the functions of many other Parkinson's disease proteins converge on mitochondria and are directly linked to mitochondrial biology (19).…”

Section: Introductionmentioning

confidence: 85%

Megadalton-sized dityrosine aggregates of α-synuclein retain high degrees of structural disorder and internal dynamics

Verzini

Shah

Theillet

et al. 2020

Preprint

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Heterogeneous aggregates of the human protein α-synuclein (αSyn) are abundantly found in Lewy body inclusions of Parkinson’s disease patients. While structural information on classical αSyn amyloid fibrils is available, little is known about the conformational properties of disease-relevant, non-canonical aggregates. Here, we analyze the structural and dynamic properties of megadalton-sized dityrosine adducts of αSyn that form in the presence of reactive oxygen species and cytochrome c, a proapoptotic peroxidase that is released from mitochondria during sustained oxidative stress. In contrast to canonical cross-β amyloids, these aggregates retain high degrees of internal dynamics, which enables their characterization by solution-state NMR spectroscopy. We find that intermolecular dityrosine crosslinks restrict αSyn motions only locally whereas large segments of concatenated molecules remain flexible and disordered. Indistinguishable aggregates form in crowded in vitro solutions and in complex environments of mammalian cell lysates, where relative amounts of free reactive oxygen species rather than cytochrome c are rate limiting. We further establish that dityrosine adducts inhibit classical amyloid formation by maintaining αSyn in its monomeric form and that they are non-cytotoxic despite retaining basic membrane-binding properties. Our results suggest that oxidative αSyn aggregation scavenges cytochrome c’s activity into the formation of amorphous, high molecular-weight structures that may contribute to aggregate diversity in Lewy body deposits.

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“…The SNAREs, syntaxin-1, SNAP-25, and synaptobrevin-2, are shown in red, gray, and blue, respectively. JBC REVIEWS: Protein disorder in vesicle traffic and release 119,[122][123][124][125][126][127][128][129][130][131][132][133]. It has further been suggested that synuclein may also function as a molecular chaperone for synaptobrevin-2, the synaptic v-SNARE (119).…”

Section: ␣-Synucleinmentioning

confidence: 99%

“…lipids with phosphatidylethanolamine headgroups) (162)(163)(164)(165)(166)(167). Synuclein thus may be optimized to bind synaptic vesicles, although it clearly interacts with other membranes as well, including possibly the plasma membrane and mitochondrial membranes (115,116,133). Interestingly, synuclein can, in some contexts, actively induce membrane curvature to remodel lipid membranes; this could have functional significance for synaptic vesicle exocytosis, which requires alterations in membrane shape and curvature prior to membrane fusion (168 -171).…”

Section: ␣-Synucleinmentioning

confidence: 99%

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Intrinsically disordered proteins in synaptic vesicle trafficking and release

Snead

Eliezer

2019

Journal of Biological Chemistry

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Edited by Norma M. Allewell 2 The abbreviations used are: IDP, intrinsically disordered protein; IDR intrinsically disordered protein region; PTM, post-translational modification; ER, endoplasmic reticulum; GAP, GTPase-activating protein; ALPS, amphipathic lipid-packing sensor; NSF, N-ethylmaleimide-sensitive factor; SNAP, soluble NSF attachment protein; NTD, N-terminal domain; CTD, C-terminal domain; AH, accessory helix; CH, central helix; SH, Src homology; RIM-BP, RIM-binding protein; Syt1, synaptotagmin-1; MARCKS, membrane-binding region of the myristoylated alanine-rich protein kinase C substrate; CaMKII, calcium/calmodulin-dependent protein kinase II; PSD, postsynaptic density; SV, synaptic vesicle; NAC, non-amyloid-beta-component.The SNARE proteins (for SNAP receptor proteins, where SNAPs are soluble NSF attachment proteins, and NSF is the N-ethylmaleimide-sensitive factor) are a superfamily of small proteins that mediate membrane fusion in all steps of cellular secretory pathways and that constitute the core membrane fusion machinery (30,31). Humans contain 36 different SNARE proteins, which are found attached to membranes, often through a C-terminal transmembrane domain, although attachment via post-translational lipidation also occurs for JBC REVIEWS: Protein disorder in vesicle traffic and release 3326 Figure 2. SNARE proteins constitute a core membrane fusion machinery wherein a disorder-to-order transition is coupled to force transfer that induces membrane fusion. The SNARE proteins associated with synaptic vesicle exocytosis are highlighted here. Initially, syntaxin-1 (red) and SNAP-25 (gray) are anchored to the plasma membrane, whereas synaptobrevin-2 (blue) is anchored to synaptic vesicles. During synaptic vesicle fusion with the plasma membrane, the disordered SNARE motifs of these three proteins assemble into a stable four-helix bundle (with two helices contributed by SNAP-25). Although still incompletely understood, the energy of SNARE complex assembly is thought to drive membrane fusion, as the complex transitions from an initial partially assembled trans-SNARE complex (with SNAREs anchored in opposing membranes), through fusion pore opening, to a final fully assembled cis-SNARE complex (with all three SNAREs now in the plasma membrane). Subsequent to membrane fusion, the cis-SNARE complex is disassembled by NSF in an ATP-dependent fashion.JBC REVIEWS: Protein disorder in vesicle traffic and release 3328

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

Cited by 24 publications

References 104 publications

The docking of synaptic vesicles on the presynaptic membrane induced by α-synuclein is modulated by lipid composition

The docking of synaptic vesicles on the presynaptic membrane induced by α-synuclein is modulated by lipid composition

Megadalton-sized dityrosine aggregates of α-synuclein retain high degrees of structural disorder and internal dynamics

Intrinsically disordered proteins in synaptic vesicle trafficking and release

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