N-acetylation of α-synuclein enhances synaptic vesicle clustering mediated by α-synuclein and lysophosphatidylcholine
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Yaoyang Zhang
PROVIDER: PXD059259 | iProX | Thu Dec 26 00:00:00 GMT 2024
REPOSITORIES: iProX
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Project description:α-Synuclein (α-syn) is an intrinsically disordered protein (IDP) that undergoes liquid-liquid phase separation (LLPS), fibrillation, and forms insoluble intracellular Lewy’s bodies in neurons, which are the hallmark of Parkinson’s Disease (PD). Neurotoxicity precedes the formation of aggregates and is probably related to LLPS of α-syn in the cell. The molecular mechanisms underlying the early stages of LLPS are still elusive. To obtain structural insights into α-syn upon LLPS, we take advantage of cross-linking/mass spectrometry (XL-MS) and introduced an innovative new approach, termed COMPASS (COMPetitive PAiring StatisticS). COMPASS unravels transient interactions between α-syn molecules in liquid droplets to derive structural information of α-syn upon LLPS. In this work, we show that the conformational ensemble of α-syn shifts towards more elongated conformational states upon LLPS. We obtain insights into the critical initial stages of PD and establish a novel mass spectrometry-based approach that will aid to solve open questions in LLPS structural biology.
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Project description:This study reveals a novel mechanism linking social isolation to anxiety through a glucocorticoid (GC)-driven, ventral hippocampal (vHip)-specific iron-α-synuclein (α-Syn) axis. Social isolation activates glucocorticoid receptors (GRs) in vHip pyramidal neurons, which upregulate transferrin receptor 1 (TfR1) to promote iron accumulation. Elevated iron induces α-Syn overexpression, thereby enhancing presynaptic glutamate release and neuronal hyperexcitability in the vHip; this ultimately drives anxiety-like behaviors. Gain-of-function/loss-of-function experiments confirm that TfR1 and α-Syn are essential for this pathway, while intranasal iron chelation or α-Syn inhibition rescues both neural and behavioral abnormalities. These findings establish the GR-TfR1-α-Syn axis as a therapeutic target for social stress-related anxiety, which bridges metallobiology and psychiatric pathophysiology.
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Project description:LC-MS/MS analyses were performed on soluble alpha-Syn purified from PD and various alpha-Synucleinopathies to systematically explore the landscape of post-translational modifications (PTMs) on soluble alpha-Syn, leading to the identification of a large number of novel alpha-Syn PTMs.
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Project description:Kuznetsov2016(II) - α-syn aggregation
kinetics in Parkinson's
This theoretical model uses 2-step Finke-Watzky (FW) kinetics
todescribe the production, misfolding, aggregation, transport and
degradation of α-syn that may lead to Parkinson's Disease
(PD). Deregulated α-syn degradation is predicted to be
crucialfor PD pathogenesis.
This model is described in the article:
What can trigger the onset
of Parkinson's disease - A modeling study based on a
compartmental model of α-synuclein transport and aggregation in
neurons.
Kuznetsov IA, Kuznetsov AV.
Math Biosci 2016 Aug; 278: 22-29
Abstract:
The aim of this paper is to develop a minimal model
describing events leading to the onset of Parkinson's disease
(PD). The model accounts for α-synuclein (α-syn) production in
the soma, transport toward the synapse, misfolding, and
aggregation. The production and aggregation of polymeric α-syn
is simulated using a minimalistic 2-step Finke-Watzky model. We
utilized the developed model to analyze what changes in a
healthy neuron are likely to lead to the onset of α-syn
aggregation. We checked the effects of interruption of α-syn
transport toward the synapse, entry of misfolded (infectious)
α-syn into the somatic and synaptic compartments, increasing
the rate of α-syn synthesis in the soma, and failure of α-syn
degradation machinery. Our model suggests that failure of α-syn
degradation machinery is probably the most likely cause for the
onset of α-syn aggregation leading to PD.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000615.
To cite BioModels Database, please use:
BioModels Database:
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quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
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Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000615 | BioModels
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Project description:α-Synuclein (α-Syn) is a protein implicated in the pathogenesis of Parkinson’s disease (PD). It is primarily cytosolic and reversibly interacts with cell membranes. α-Syn also occurs in the nucleus, however, the mechanisms involved in its nuclear localization are poorly understood. We analyzed alterations in gene expression following induced α-Syn expression in SH-SY5Y cells. Analysis for upstream regulators pointed at alterations in transcription activity of retinoic acid receptors (RAR)s and additional nuclear receptors. We show that α-Syn binds RA and translocates to the nucleus to selectively enhance gene transcription. Nuclear translocation of α-Syn is regulated by calreticulin, in a leptomycin-B independent mechanism. Importantly, nuclear translocation of α-Syn following RA treatment enhances its toxicity in cultured neurons and the expression levels of PD-associated genes, among which are two familial PDassociated genes, ATPase cation transporting 13A2 (ATP13A2) and PTEN-induced kinase 1 (PINK1). The results link a physiological role for α-Syn in the regulation of RAmediated gene transcription and its toxicity in the synucleinopathies.
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2019-08-12 | GSE130683 | GEO
Project description:LC-MS/MS analyses were performed on soluble alpha-Syn purified from PD and various alpha-Synucleinopathies to systematically explore the landscape of post-translational modifications (PTMs) on soluble alpha-Syn, leading to the identification of a large number of novel alpha-Syn PTMs.
2023-02-02 | PXD037994 | Pride
Project description:Cross-linking mass spectrometry (XL-MS) is a powerful tool for studying protein-protein interactions and elucidating architectures of protein complexes. While residue-specific XL-MS studies have been very successful, accessibility of interaction regions non-targetable by specific chemistries remain difficult. Photochemistry has shown great potential in capturing those regions due to nonspecific reactivity, but low yields and high complexities of photocross-linked products have hindered their identification, limiting current studies predominantly to single proteins. Here, we describe the development of three novel MS-cleavable heterobifunctional cross-linkers, namely SDASO (Succinimidyl diazirine sulfoxide), to enable fast and accurate identification of photocross-linked peptides by MSn. The MSn-based workflow allowed SDASO XL-MS analysis of the yeast 26S proteasome, demonstrating the feasibility of photocross-linking of large protein complexes for the first time. Comparative analyses have revealed that SDASO cross-linking is robust and captures interactions complementary to residue-specific reagents, providing the foundation for future applications of photocross-linking in complex XL-MS studies.
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