The role of RNA in the nanoscale organization of alpha-synuclein phase separation DOI Creative Commons
Sabrina Zappone, Eleonora Perego, Jakob Rupert

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 3, 2024

The accumulation of alpha-synuclein (aS) protein aggregates in cells is a typical hallmark several neurodegenerative diseases. Recent studies have shown that the aberrant transition monomeric aS into solid-like can occur via an intermediate liquid-like state, where partitions between dense and dilute phases. Although not typically recognized as RNA-binding protein, it bind RNA under aggregation conditions. However, impact on dynamics within phases remains unclear. Here, we employ combination fluorescence spectroscopy techniques to explore both presence RNA. Our sensitive analysis phase revealed formation precursor nanoclusters involved initiating separation. We also uncovered heterogeneity phase, discovering molecules exist two distinct mobility states: freely diffusing or confined micro-domains. Additionally, was found induce morphological changes phase. quantitative analysis, based lifetime measurements, showed alters properties promoting liquid-to-solid transition. These findings indicate active role modulating material influencing its transitions.

Language: Английский

VAMP2 chaperones α-synuclein in synaptic vesicle co-condensates DOI
Chuchu Wang, Kai Zhang, Bin Cai

et al.

Nature Cell Biology, Journal Year: 2024, Volume and Issue: 26(8), P. 1287 - 1295

Published: July 1, 2024

Language: Английский

Citations

16
A Single Amino Acid Model for Hydrophobically Driven Liquid–Liquid Phase Separation DOI
Heung Bae Jeon, Joo Hyung Lee,

A.J. Park

et al.

Biomacromolecules, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 26, 2025

This study proposes fluorenylmethoxycarbonyl (Fmoc)-protected single amino acids (Fmoc-AAs) as a minimalistic model system to investigate liquid-liquid phase separation (LLPS) and the elusive liquid-to-solid transition of condensates. We demonstrated that Fmoc-AAs exhibit LLPS depending on pH ionic strength, primarily driven by hydrophobic interactions. Systematic examination conditions under which each Fmoc-AA undergoes revealed distinct residue-dependent trends in critical concentrations behavior. Importantly, we elucidated process, suggesting it may be molecular mechanism different from LLPS. condensates showed promise for biomolecular enrichment catalytic applications. work provides significant insights into mechanisms subsequent transition, offering robust platform future studies related protocells protein aggregation diseases.

Language: Английский

Citations

1
Pathological Involvement of Protein Phase Separation and Aggregation in Neurodegenerative Diseases DOI Open Access
Y. Wu, Biao Ma, Chang Yu Liu

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(18), P. 10187 - 10187

Published: Sept. 23, 2024

Neurodegenerative diseases are the leading cause of human disability and immensely reduce patients’ life span quality. The characterized by functional loss neuronal cells share several common pathogenic mechanisms involving malfunction, structural distortion, or aggregation multiple key regulatory proteins. Cellular phase separation is formation biomolecular condensates that regulate numerous biological processes, including development synaptic signaling transduction. Aberrant may protein a general phenomenon in patients suffering neurodegenerative diseases. In this review, we summarize pathological causes diseases, Alzheimer’s disease, Parkinson’s Huntington’s among others. We discuss regulation amyloidogenic proteins with an emphasis their aberrant aggregation. also introduce approaches as potential therapeutic strategies to ameliorate through intervening Overall, review consolidates research findings caused misfolded context

Language: Английский

Citations

4
Synaptotagmin-1 undergoes phase separation to regulate its calcium-sensitive oligomerization DOI Creative Commons
Min Zhu,

Han Xu,

Yulei Jin

et al.

The Journal of Cell Biology, Journal Year: 2024, Volume and Issue: 223(10)

Published: July 9, 2024

Synaptotagmin-1 (Syt1) is a calcium sensor that regulates synaptic vesicle fusion in synchronous neurotransmitter release. Syt1 interacts with negatively charged lipids and the SNARE complex to control event. However, it remains incompletely understood how mediates Ca2+-trigged fusion. Here, we discovered undergoes liquid-liquid phase separation (LLPS) form condensates both vitro living cells. play role attachment PM efficiently recruit SNAREs complexin, which may facilitate downstream We observed undergo liquid-to-gel-like transition, reflecting formation of oligomers. The transition can be blocked or reversed by Ca2+, confirming essential Ca2+ oligomer disassembly. Finally, showed mutations causing Syt1-associated neurodevelopmental disorder impair Ca2+-driven transition. These findings reveal LLPS Ca2+-sensitive providing new insights into Syt1-mediated

Language: Английский

Citations

3
Human cerebral organoids model tumor infiltration and migration supported by astrocytes in an autologous setting DOI Open Access

Esther Schickel,

Tamara Bender,

Leon Kaysan

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 29, 2025

Summary Efforts to achieve precise and efficient tumor targeting of highly malignant brain tumors are constrained by the dearth appropriate models study effects potential side radiation, chemotherapy, immunotherapy on most complex human organ, brain. We established a cerebral organoid model tumorigenesis in an autologous setting overexpressing c-MYC as one common oncogenes tumors. GFP + /c-MYC high cells were isolated from organoids used two different culture approaches: assembloids comprising normal with sphere co-culture slices at air-liquid interface cells. both approaches exhibited tumor-like properties, including overexpression oncogene, proliferative invasive potential, immature phenotype evidenced increased expression Ki-67, VIM, CD133. Organoids served suitable scaffolds for infiltrating Using our reproducible powerful system that allows long-term culture, we demonstrated migratory infiltrative is shaped environment which glia provide support

Language: Английский

Citations

0
A novel alpha-synuclein K58N missense variant in a patient with Parkinson's disease DOI Creative Commons
Mohammed Al-Azzani, Sandrina Weber, Nagendran Ramalingam

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 13, 2025

Mutations and multiplications in the SNCA gene , encoding alpha-synuclein (aSyn), are associated with familial forms of Parkinson's disease (PD). We report identification a novel missense mutation (NM_000345.4, cDNA 174G>C; protein K58N) PD patient using whole exome sequencing, describe comprehensive molecular cellular analysss effects this mutation. The exhibited typical sporadic early onset benign course. Biophysical studies revealed that K58N substitution causes local structural effects, disrupts binding to membranes, enhances aSyn vitro aggregation. produces fewer inclusions per cell, fails undergo condensate formation. increases cytoplasmic distribution protein, has minimal effect on dynamic reversibility serine-129 phosphorylation. In total, advances our understanding biology pathobiology.

Language: Английский

Citations

0
The Role of Membrane-Biomolecular Condensate Interactions in Stress DOI Creative Commons
Konstantin Kutashev, Panagiotis N. Moschou

Plant Stress, Journal Year: 2025, Volume and Issue: unknown, P. 100810 - 100810

Published: March 1, 2025

Language: Английский

Citations

0
Role of glial cells in neurotoxicological effects of alcohol DOI
Yousef Tizabi, Bruk Getachew, Michael Aschner

et al.

Advances in neurotoxicology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

0
α-Synuclein condensation in synaptic vesicle function and synucleinopathies DOI
Dan Li, Kaien Liu, Danni Li

et al.

Trends in Cell Biology, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

Citations

0
Increased burden of rare risk variants across gene expression networks predisposes to sporadic Parkinson’s disease DOI Creative Commons

Elena Eubanks,

Katelyn VanderSleen,

Jiya Mody

et al.

Cell Reports, Journal Year: 2025, Volume and Issue: 44(5), P. 115636 - 115636

Published: May 1, 2025

Alpha-synuclein (αSyn) is an intrinsically disordered protein that accumulates in the brains of patients with Parkinson's disease (PD). Through a high-throughput screen, we recently identified 38 genes whose knockdown modulates αSyn propagation. Here, show that, among those, TAX1BP1 regulates how interacts lipids, and ADAMTS19 phase separates into inclusions, adding to growing body evidence implicating those processes PD. RNA sequencing, identify several are differentially expressed after or carry increased frequency rare risk variants PD versus healthy controls. Those cluster within modules regions brain develop high degrees pathology. We propose model for genetic architecture sporadic PD: burden across networks dysregulates pathways underlying homeostasis leads pathology neurodegeneration.

Language: Английский

Citations

0