β-synuclein regulates the phase transitions and amyloid conversion of α-synuclein DOI Creative Commons

Xi Li,

Linwei Yu, Xikai Liu

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Oct. 9, 2024

Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB) are neurodegenerative disorders characterized by the accumulation of α-synuclein aggregates. forms droplets via liquid-liquid phase separation (LLPS), followed liquid-solid (LSPS) to form amyloids, how this process is physiologically-regulated remains unclear. β-synuclein colocalizes in presynaptic terminals. Here, we report that partitions into condensates promotes LLPS, slows down LSPS α-synuclein, while disease-associated mutations lose these capacities. Exogenous improves movement defects prolongs lifespan an α-synuclein-expressing NL5901 Caenorhabditis elegans strain, mutants aggravate symptoms. Decapeptides targeted at α-/β-synuclein interaction sites rationally designed, which suppress rescue defects, prolong C. NL5901. Together, unveil a Yin-Yang balance between α- underlying normal states PD DLB therapeutical potentials.

Language: Английский

Manganese‐Based Tumor Immunotherapy DOI
Ke Zhang, Chao Qi, Kaiyong Cai

et al.

Advanced Materials, Journal Year: 2022, Volume and Issue: 35(19)

Published: Sept. 19, 2022

Abstract As an essential micronutrient, manganese (Mn) participates in various physiological processes and plays important roles host immune system, hematopoiesis, endocrine function, oxidative stress regulation. Mn‐based nanoparticles are considered to be biocompatible show versatile applications nanomedicine, particular utilized tumor immunotherapy the following ways: 1) acting as a nanocarrier deliver immunotherapeutic agents for immunotherapy; 2) serving adjuvant regulate microenvironment enhance 3) activating host's system through cGAS‐STING pathway trigger 4) real‐time monitoring effect by magnetic resonance imaging (MRI) since Mn 2+ ions ideal MRI contrast agent which can significantly T 1 ‐weighted signal after binding proteins. This comprehensive review focuses on most recent progress of nanoplatforms immunotherapy. The characteristics first discussed guide design multifunctional nanoplatforms. Then biomedical nanoplatforms, including alone, immunotherapy‐involved multimodal synergistic therapy, imaging‐guided detail. Finally, challenges future developments highlighted.

Language: Английский

Citations

168
Liquid-liquid Phase Separation of α-Synuclein: A New Mechanistic Insight for α-Synuclein Aggregation Associated with Parkinson's Disease Pathogenesis DOI Open Access
Semanti Mukherjee, Arunima Sakunthala, Laxmikant Gadhe

et al.

Journal of Molecular Biology, Journal Year: 2022, Volume and Issue: 435(1), P. 167713 - 167713

Published: July 3, 2022

Language: Английский

Citations

83
Mass photometric detection and quantification of nanoscale α-synuclein phase separation DOI
Soumik Ray, Thomas O. Mason, Lars Boyens‐Thiele

et al.

Nature Chemistry, Journal Year: 2023, Volume and Issue: 15(9), P. 1306 - 1316

Published: June 19, 2023

Language: Английский

Citations

68
Protein misfolding and amyloid nucleation through liquid–liquid phase separation DOI
S. Mukherjee, Manisha Poudyal, K. Dave

et al.

Chemical Society Reviews, Journal Year: 2024, Volume and Issue: 53(10), P. 4976 - 5013

Published: Jan. 1, 2024

Protein misfolding and amyloid aggregation, linked to neurodegenerative diseases, can result from liquid–liquid phase separation (LLPS) a subsequent liquid-to-solid transition. This represents LLPS as generic mechanism in nucleation.

Language: Английский

Citations

25
Direct Observation of “Elongated” Conformational States in α‐Synuclein upon Liquid‐Liquid Phase Separation DOI Creative Commons

Daniele Ubbiali,

Marta Fratini, Lolita Piersimoni

et al.

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 61(46)

Published: Sept. 17, 2022

Abstract α‐Synuclein (α‐syn) is an intrinsically disordered protein (IDP) that undergoes liquid‐liquid phase separation (LLPS), fibrillation, and forms insoluble intracellular Lewy bodies in neurons, which are the hallmark of Parkinson's Disease (PD). Neurotoxicity precedes formation aggregates might be related to α‐syn LLPS. The molecular mechanisms underlying early stages LLPS still elusive. To obtain structural insights into upon LLPS, we take advantage cross‐linking/mass spectrometry (XL–MS) introduce innovative approach, termed COMPASS (COMPetitive PAiring StatisticS). In this work, show conformational ensemble shifts from a “hairpin‐like” structure towards more “elongated” states We critical initial establish novel mass spectrometry‐based approach will aid solve open questions biology.

Language: Английский

Citations

43
Calcium promotes α-synuclein liquid-liquid phase separation to accelerate amyloid aggregation DOI
Shuai Huang,

Bingkuan Xu,

Yinghui Liu

et al.

Biochemical and Biophysical Research Communications, Journal Year: 2022, Volume and Issue: 603, P. 13 - 20

Published: Feb. 25, 2022

Language: Английский

Citations

40
Development of Small Molecules Targeting α-Synuclein Aggregation: A Promising Strategy to Treat Parkinson’s Disease DOI Creative Commons
Samuel Peña‐Díaz, Javier García‐Pardo, Salvador Ventura

et al.

Pharmaceutics, Journal Year: 2023, Volume and Issue: 15(3), P. 839 - 839

Published: March 3, 2023

Parkinson’s disease, the second most common neurodegenerative disorder worldwide, is characterized by accumulation of protein deposits in dopaminergic neurons. These are primarily composed aggregated forms α-Synuclein (α-Syn). Despite extensive research on this only symptomatic treatments currently available. However, recent years, several compounds, mainly an aromatic character, targeting α-Syn self-assembly and amyloid formation have been identified. discovered different approaches, chemically diverse exhibit a plethora mechanisms action. This work aims to provide historical overview physiopathology molecular aspects associated with disease current trends small compound development target aggregation. Although these molecules still under development, they constitute important step toward discovering effective anti-aggregational therapies for disease.

Language: Английский

Citations

27
Structure–Toxicity Relationship in Intermediate Fibrils from α-Synuclein Condensates DOI Creative Commons
Serene W. Chen, Joseph D. Barritt, Roberta Cascella

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(15), P. 10537 - 10549

Published: April 3, 2024

The aberrant aggregation of α-synuclein (αS) into amyloid fibrils is associated with a range highly debilitating neurodegenerative conditions, including Parkinson's disease. Although the structural properties mature amyloids αS are currently understood, nature transient protofilaments and that appear during remains elusive. Using solid-state nuclear magnetic resonance (ssNMR), cryogenic electron microscopy (cryo-EM), biophysical methods, we here characterized intermediate forming from liquid-like spherical condensates to adopting structure pathologically observed aggregates. These intermediates, which induce significant levels cytotoxicity when incubated neuronal cells, were found be stabilized by small core in an antiparallel β-sheet conformation, disordered N-terminal region protein remaining available mediate membrane binding. In contrast, subsequently showed different biological properties, low cytotoxicity, rearranged structured embedding also region, reduced propensity interact membrane. characterization these two fibrillar forms αS, use antibodies designed mutants, enabled us clarify role critical elements endowing species ability membranes cytotoxicity.

Language: Английский

Citations

14
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

12
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