Phase Separation and Aggregation of α‐Synuclein Diverge at Different Salt Conditions DOI Creative Commons
Rebecca Sternke‐Hoffmann,

Xun Sun,

Andreas Menzel

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: unknown

Published: July 7, 2024

The coacervation of alpha-synuclein (αSyn) into cytotoxic oligomers and amyloid fibrils are considered pathological hallmarks Parkinson's disease. While aggregation is central to diseases, liquid-liquid phase separation (LLPS) its interplay with have gained increasing interest. Previous work shows that factors promoting or inhibiting similar effects on LLPS. This study provides a detailed scanning wide range parameters, including protein, salt crowding concentrations at multiple pH values, revealing different dependencies influence under conditions follows non-monotonic pattern, showing increased medium concentrations. behavior can be elucidated through combination electrostatic screening salting-out the intramolecular interactions between N-terminal C-terminal regions αSyn. By contrast, this finds monotonic dependence LLPS due intermolecular interactions. Furthermore, it observes time evolution two distinct assembly states, macroscopic fibrillar-like bundles initially forming concentration but subsequently converting droplets after prolonged incubation. droplet state therefore capable even dissolving aggregates heterotypic interactions, thus preventing αSyn from dynamically arrested state.

Language: Английский

VAMP2 regulates phase separation of α-synuclein DOI Creative Commons
Aishwarya Agarwal, Aswathy Chandran,

Farheen Raza

et al.

Nature Cell Biology, Journal Year: 2024, Volume and Issue: 26(8), P. 1296 - 1308

Published: July 1, 2024

α-Synuclein (αSYN), a pivotal synaptic protein implicated in synucleinopathies such as Parkinson's disease and Lewy body dementia, undergoes phase separation. We reveal that vesicle-associated membrane 2 (VAMP2) orchestrates αSYN separation both vitro cells. Electrostatic interactions, specifically mediated by VAMP2 via its juxtamembrane domain the C-terminal region, drive Condensate formation is specific for R-SNARE dependent on lipid binding. Our results delineate regulatory mechanism Furthermore, we show condensates sequester vesicles attract complexin-1 -2, thus supporting role physiology pathophysiology.

Language: Английский

Citations

14
CYP1B1 affects the integrity of the blood–brain barrier and oxidative stress in the striatum: An investigation of manganese‐induced neurotoxicity DOI Creative Commons
Juan Wu,

Yueran Li,

Shuwei Tian

et al.

CNS Neuroscience & Therapeutics, Journal Year: 2024, Volume and Issue: 30(3)

Published: March 1, 2024

Abstract Aims Excessive influx of manganese (Mn) into the brain across blood–brain barrier induces neurodegeneration. CYP1B1 is involved in metabolism arachidonic acid (AA) that affects vascular homeostasis. We aimed to investigate effect on Mn‐induced neurotoxicity. Method Brain Mn concentrations and α‐synuclein accumulation were measured wild‐type knockout mice treated with MnCl 2 (30 mg/kg) biotin (0.2 g/kg) for 21 continuous days. Tight junctions oxidative stress analyzed hCMEC/D3 SH‐SY5Y cells after treatment (200 μM) CYP1B1‐derived AA metabolites (HETEs EETs). Results exposure inhibited CYP1B1, deficiency increased accelerated deposition striatum. disrupted integrity (BBB) ratio 3, 4‐dihydroxyphenylacetic (DOPAC) dopamine HETEs attenuated inhibition tight by activating PPARγ endothelial cells. Additionally, EETs up‐regulation KLF/MAO‐B axis down‐regulation NRF2 neuronal Biotin up‐regulated reduced neurotoxicity mice. Conclusions plays a critical role both cerebrovascular homeostasis, which might serve as novel therapeutic target prevention

Language: Английский

Citations

10
Myricetin Inhibits α‐Synuclein Amyloid Aggregation by Delaying the Liquid‐to‐Solid Phase Transition DOI

Bingkuan Xu,

Xiaoli Mo, Jing Chen

et al.

ChemBioChem, Journal Year: 2022, Volume and Issue: 23(16)

Published: June 3, 2022

The aggregation of α-synuclein (α-Syn) is a critical pathological hallmark Parkinson's disease (PD). Prevention α-Syn has become key strategy for treating PD. Recent studies have suggested that undergoes liquid-liquid phase separation (LLPS) to facilitate nucleation and amyloid formation. Here, we examined the modulation by myricetin, polyhydroxyflavonol compound, under conditions LLPS. Unexpectedly, neither initial morphology nor phase-separated fraction was altered myricetin. However, dynamics condensates decreased upon myricetin binding. Further showed dose-dependently inhibits in delaying liquid-to-solid transition. In addition, could disassemble preformed aggregates matured from condensates. Together, our study shows retarding transition reveals can be targeted inhibit aggregation.

Language: Английский

Citations

29
Small molecules in regulating protein phase separation DOI Creative Commons
Siyang Li, Yanyan Wang, Luhua Lai

et al.

Acta Biochimica et Biophysica Sinica, Journal Year: 2023, Volume and Issue: 55(7), P. 1075 - 1083

Published: June 1, 2023

Biomolecular condensates formed by phase separation are involved in many cellular processes. Dysfunctional or abnormal closely associated with neurodegenerative diseases, cancer and other diseases. Small molecules can effectively regulate protein modulating the formation, dissociation, size material properties of condensates. Discovery small to provides chemical probes for deciphering underlying mechanism potential novel treatments condensate-related Here we review advances molecule regulation separation. The discovery, structures recently found regulators how they modulate biological summarized discussed. Possible strategies accelerate discovery more liquid-liquid (LLPS)-regulating proposed.

Language: Английский

Citations

21
α-Synuclein liquid condensates fuel fibrillar α-synuclein growth DOI Creative Commons
Leonard Piroska, Alexis Fenyi,

Scott E. Thomas

et al.

Science Advances, Journal Year: 2023, Volume and Issue: 9(33)

Published: Aug. 16, 2023

α-Synuclein (α-Syn) aggregation into fibrils with prion-like features is intimately associated Lewy pathology and various synucleinopathies. Emerging studies suggest that α-Syn could form liquid condensates through phase separation. The role of these in disease remains elusive the interplay between unexplored, possibly due to difficulties triggering formation cells. To address this gap, we developed an assay allowing controlled assembly/disassembly cells studied them upon exposure preformed fibrillar polymorphs. Fibrils triggered evolution solid-like structures displaying growing needle-like extensions exhibiting pathological amyloid hallmarks. No such changes were elicited on did not undergo We, therefore, propose a model where within fuels exogenous seeds growth, thus speeding up propagation pathogenic aggregates.

Language: Английский

Citations

17
Liquid–liquid phase separation of α‐synuclein is highly sensitive to sequence complexity DOI
Anindita Mahapatra, Robert W. Newberry

Protein Science, Journal Year: 2024, Volume and Issue: 33(4)

Published: March 21, 2024

The Parkinson's-associated protein α-synuclein (α-syn) can undergo liquid-liquid phase separation (LLPS), which typically leads to the formation of amyloid fibrils. coincidence LLPS and has complicated identification molecular determinants unique α-syn. Moreover, lack strategies selectively perturb makes it difficult dissect biological roles specific α-syn LLPS, independent fibrillation. Herein, using a combination subtle missense mutations, we show that is highly sensitive its sequence complexity. In fact, find even conservative mutation (V16I) increases complexity without perturbing physicochemical structural properties, sufficient reduce by 75%; this effect be reversed an adjacent V-to-I (V15I) restores original A18T, complexity-enhancing PD-associated mutation, was likewise found implicating in pathogenicity. Furthermore, leveraging differences propensities among different variants, demonstrate fibrillation does not necessarily correlate with LLPS. identify mutations or α-syn, unlike previously studied mutations. variants design principles reported herein should therefore empower future studies disentangle these two phenomena distinguish their (patho)biological roles.

Language: Английский

Citations

8
α‐Synuclein phase separation and amyloid aggregation are modulated by C‐terminal truncations DOI
Shuai Huang, Xiaoli Mo, Jieyi Wang

et al.

FEBS Letters, Journal Year: 2022, Volume and Issue: 596(11), P. 1388 - 1400

Published: April 29, 2022

The aggregation of α-synuclein (α-Syn) is a key pathological hallmark Parkinson's disease (PD). α-Syn undergoes liquid-liquid phase separation (LLPS) to drive amyloid aggregation. How the LLPS regulated remains largely unknown. Here, we discovered that C-terminal region modulates through electrostatic interactions. wild-type (WT) and PD disease-related truncated can co-exist in condensates. could dramatically promote WT separation. Further studies demonstrated accelerated turning aggregates by modulation Together, our findings disclose role domain pave path for understanding mechanism pathology.

Language: Английский

Citations

27
Structural Insights of Fe3+ Induced α-synuclein Fibrillation in Parkinson’s Disease DOI Open Access

Qinyue Zhao,

Youqi Tao,

Kun Zhao

et al.

Journal of Molecular Biology, Journal Year: 2022, Volume and Issue: 435(1), P. 167680 - 167680

Published: June 8, 2022

Language: Английский

Citations

23
Multifunctional Metallothioneins as a Target for Neuroprotection in Parkinson’s Disease DOI Creative Commons
Ikuko Miyazaki, Masato Asanuma

Antioxidants, Journal Year: 2023, Volume and Issue: 12(4), P. 894 - 894

Published: April 6, 2023

Parkinson's disease (PD) is characterized by motor symptoms based on a loss of nigrostriatal dopaminergic neurons and non-motor which precede symptoms. Neurodegeneration accompanied an accumulation α-synuclein thought to propagate from the enteric nervous system central system. The pathogenesis in sporadic PD remains unknown. However, many reports indicate various etiological factors, such as oxidative stress, inflammation, toxicity mitochondrial impairment, drive neurodegeneration. Exposure heavy metals contributes these etiopathogenesis increases risk developing PD. Metallothioneins (MTs) are cysteine-rich metal-binding proteins; MTs chelate inhibit metal-induced inflammation dysfunction. In addition, possess antioxidative properties scavenging free radicals exert anti-inflammatory effects suppression microglial activation. Furthermore, recently received attention potential target for attenuating aggregation. this article, we summarize expression system, review protective functions against We also discuss neuroprotective strategies prevention neurodegeneration targeting MTs. This highlights multifunctional development disease-modifying drugs

Language: Английский

Citations

14
Posttranslational Modifications ofα-Synuclein, Their Therapeutic Potential, and Crosstalk in Health and Neurodegenerative Diseases DOI
Kambiz Hassanzadeh, Jun Liu,

Santhosh Chandar Maddila

et al.

Pharmacological Reviews, Journal Year: 2024, Volume and Issue: 76(6), P. 1254 - 1290

Published: Oct. 16, 2024

α-Synuclein (α-Syn) aggregation in Lewy bodies and neurites has emerged as a key pathogenetic feature Parkinson's disease, dementia with bodies, multiple system atrophy. Various factors, including posttranslational modifications (PTMs), can influence the propensity of α-Syn to misfold aggregate. PTMs are biochemical protein that occur during or after translation typically mediated by enzymes. modulate several characteristics proteins their structure, activity, localization, stability. undergoes various modifications, phosphorylation, ubiquitination, SUMOylation, acetylation, glycation, O-GlcNAcylation, nitration, oxidation, polyamination, arginylation, truncation. Different physically interact one another work together particular physiological pathological process known crosstalk. The development detection techniques for cooccurrence recent years uncovered previously unappreciated mechanisms This led emergence evidence supporting an association between crosstalk synucleinopathies. In this review, we provide comprehensive evaluation PTMs, impact on misfolding pathogenicity, pharmacological means targeting them, potential biomarkers disease. We also highlight importance these function aggregation. Insight into PTMS complexities improve our understanding pathogenesis synucleinopathies identify novel targets therapeutic potential. SIGNIFICANCE STATEMENT: is pathogenic disease other synucleinopathies, making it leading target modification. Multiple at sites alter its biophysical properties, some interacting add complexity pathogenicity protein. review details implications opportunities.

Language: Английский

Citations

6