Spinal cord phosphoproteome of a SCA2/ALS13 mouse model reveals alteration of ATXN2-N-term SH3-actin interactome and of autophagy via WNK1-MYO6-OPTN-SQSTM1 DOI Open Access
Luis E. Almaguer-Mederos, Arvind Reddy Kandi,

Nesli-Ece Şen

et al.

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

Published: Nov. 6, 2024

Abstract Toxic polyglutamine (polyQ) expansions in ATXN2 trigger neurodegenerative processes, causing Spinocerebellar Ataxia type 2 (SCA2), and enhancing TDP-43-dependent pathology Amyotrophic Lateral Sclerosis (ALS) / Fronto-Temporal Dementia (FTD). Primary disease events can be compensated transiently, delaying manifestation. To define potential therapy targets, we documented how cells modify their phospho-signals the interactome changes, using preferentially affected nervous tissues from end-stage Atxn2 -CAG100-KnockIn mice. The spinal cord phosphorylome revealed massive hyperphosphorylations flanking polyQ expansion for SQSTM1, moderate also ALS proteins OPTN, UBQLN2, TNIP1 TBK1-targeted TAX1BP1, versus strong hypophosphorylations of WNK1, SPARCL1 PSMD9. Significant enrichments SH3-containing proteins, autophagy endocytosis factors, actin modulators could explained by N-terminal, polyQ-adjacent, proline-rich motifs ATXN2. Coimmunoprecipitation profiling cerebellum known associations with RNA-binding like PABPC1 TDP-43 its modifier PPIA to decrease upon expansion, contrasting increased binding SH3-proteins, MYO6, RPL21 DLG4. Validation protein mRNA levels mouse cord, embryonic fibroblasts or patient after bafilomycin arsenite treatment, observed polyQ-dependent OPTN deficiency SQSTM1 induction impairment. Overall, this combined phosphoproteome study efficiently key pathways molecular events.

Language: Английский

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

26
Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review DOI Creative Commons
J Yang,

Weijia Zhi,

Lifeng Wang

et al.

Molecules, Journal Year: 2024, Volume and Issue: 29(12), P. 2812 - 2812

Published: June 13, 2024

Tau protein is a microtubule-associated that widely distributed in the central nervous system and maintains regulates neuronal morphology function. aggregates abnormally forms neurofibrillary tangles neurodegenerative diseases, disrupting structure function of neurons leading to death, which triggers initiation progression neurological disorders. The aggregation tau diseases associated with post-translational modifications, may affect hydrophilicity, spatial conformation, stability protein, promoting formation tangles. Therefore, studying role mechanism aberrant important for understanding finding therapeutic approaches. This review describes possible mechanisms by promotes modifications influencing factors, current status drug discovery development related contribute new approaches alleviate or treat diseases.

Language: Английский

Citations

18
Liquid–liquid phase separation in Alzheimer’s disease DOI
Qinggang Fu, Bixiang Zhang,

Xiaoping Chen

et al.

Journal of Molecular Medicine, Journal Year: 2024, Volume and Issue: 102(2), P. 167 - 181

Published: Jan. 2, 2024

Language: Английский

Citations

11
Coronavirus accessory protein ORF3 biology and its contribution to viral behavior and pathogenesis DOI Creative Commons
Fusheng Si, Shuai Song,

Ruisong Yu

et al.

iScience, Journal Year: 2023, Volume and Issue: 26(4), P. 106280 - 106280

Published: Feb. 28, 2023

Coronavirus porcine epidemic diarrhea virus (PEDV) is classified in the genus Alphacoronavirus, family Coronaviridae that encodes only accessory protein, ORF3 protein. However, how contributes to viral pathogenicity, adaptability, and replication obscure. In this review, we summarize current knowledge identify gaps many aspects of protein PEDV, with emphasis on its unique biological features, including membrane topology, Golgi retention mechanism, potential intrinsic disordered property, functional motifs, glycosylation, codon usage phenotypes related genetic evolution gene expression. addition, propose intriguing questions hope stimulate further studies encourage collaboration among virologists worldwide provide constructive about characteristics functions by which their role clarifying behavior pathogenesis can be possible.

Language: Английский

Citations

18
Polycatechols inhibit ferroptosis and modulate tau liquid–liquid phase separation to mitigate Alzheimer's disease DOI
Hariharan Moorthy, Madhu Ramesh,

Dikshaa Padhi

et al.

Materials Horizons, Journal Year: 2024, Volume and Issue: 11(13), P. 3082 - 3089

Published: Jan. 1, 2024

Polycatechols modulate amyloid-associated toxicities, arrest labile iron, inhibit lipid peroxidation, and regulate tau liquid–liquid phase separation (LLPS) to mitigate the pathological nexus between ferroptosis AD.

Language: Английский

Citations

9
Utilizing liquid-liquid biopolymer regulators to predict the prognosis and drug sensitivity of hepatocellular carcinoma DOI Creative Commons
Jianhao Li, Han Chen, Lang Bai

et al.

Biology Direct, Journal Year: 2025, Volume and Issue: 20(1)

Published: Jan. 6, 2025

Liquid-liquid phase separation (LLPS) is essential for the formation of membraneless organelles and significantly influences cellular compartmentalization, chromatin remodeling, gene regulation. Previous research has highlighted critical function liquid-liquid biopolymers in development hepatocellular carcinoma (HCC). This study conducted a comprehensive review 3,685 biopolymer regulators, leading to LLPS related Prognostic Risk Score (LPRS) HCC through bootstrap-based univariate Cox, Random Survival Forest (RSF), LASSO analyses. A prognostic nomogram patients was developed using LPRS other clinicopathological factors. We utilized SurvSHAP identify key genes within influencing prognosis. To validate our findings, we collected 49 cases along with adjacent tissue samples confirmed correlation between DCAF13 expression progression qRT-PCR analysis vitro experiments. established 8 LLPS-related (TXN, CBX2, DCAF13, SLC2A1, KPNA2, FTCD, MAPT, SAC3D1). Further indicated that high closely associated vascular invasion, histological grade (G3-G4), TNM stage (III-IV) HCC, concurrently establishing as an independent risk factor integrates staging patient age markedly improves predictive accuracy survival outcomes patients. Our findings suggest increased plays crucial role cancer angiogenesis. Navitoclax emerged promising treatment levels, offering novel therapeutic direction by targeting LLPS. have formulated model capable accurately predicting clinical prognosis drug sensitivity HCC. might play pivotal malignant mediated

Language: Английский

Citations

1
Phosphorylation-Induced Self-Coacervation versus RNA-Assisted Complex Coacervation of Tau Proteins DOI Creative Commons

Mohammadreza Allahyartorkaman,

Ting-Hsuan Chan,

Hsin‐Liang Chen

et al.

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: March 12, 2025

In this study, the role of phosphorylation in liquid–liquid phase separation (LLPS) tau, underlying driving forces, and potential implications on protein conformation subsequent aggregation were investigated. We compared vivo-produced phosphorylated tau (p-tau) nonphosphorylated under different coacervation conditions without adding crowding agents. Our findings revealed that spontaneous occurs exclusively p-tau, triggered by a temperature shift from 4 °C to room temperature, is driven electrostatic hydrophobic interactions. The p-tau self-acervation reversible with changes. Native mass spectrometry detects only two nine phosphate groups per molecule, highlighting impact tau's structural flexibility. Cross-linking showed fewer long-range contacts suggesting looser induced phosphorylation. Phosphorylation-induced LLPS RNA-induced occurred at timeframes. However, neither nor formed fibrils addition dextran sulfate or RNA as inducers. Using human kidney epithelial cells expressing R domain fused fluorescent proteins reporter cells, we observed aggregates nuclear envelope (NE) treated LLPS-state which correlates NE occurrences reported Alzheimer's disease brain sections. These provide deeper insights into through an intermediate condensation phase, offering novel perspectives neurodegenerative mechanisms.

Language: Английский

Citations

1
Biphasic modulation of tau liquid–liquid phase separation by polyphenols DOI
Hariharan Moorthy,

Nimsha Kamala,

Madhu Ramesh

et al.

Chemical Communications, Journal Year: 2024, Volume and Issue: 60(32), P. 4334 - 4337

Published: Jan. 1, 2024

Polyphenols, notably gallic acid (GA), act as a biphasic modulator of tau liquid–liquid phase separation in concentration-dependent manner. GA accelerates the sol-to-gel transition and inhibits aggregate-associated toxicity.

Language: Английский

Citations

6
Liquid − liquid phase separation of tau: Driving forces, regulation, and biological implications DOI Creative Commons
Ping Li, Jingxin Chen, Xi Wang

et al.

Neurobiology of Disease, Journal Year: 2023, Volume and Issue: 183, P. 106167 - 106167

Published: May 23, 2023

The past 15 years have witnessed an explosion in the studies of biomolecular condensates that are implicated numerous biological processes and play vital roles human health diseases. Recent findings demonstrate microtubule-associated protein tau forms liquid through liquid–liquid phase separation (LLPS) vitro experiments using purified recombinant proteins cell-based experiments. Although vivo lacking, emerged as important assembly state physiological pathological LLPS can regulate function microtubules, mediate stress granule formation, accelerate amyloid aggregation. In this review, we summarize recent advances LLPS, aiming to unveiling delicate interactions driving LLPS. We further discuss association with physiology disease context sophisticated regulation Deciphering mechanisms underlying liquid-to-solid transition enables rational design molecules inhibit or delay formation solid species, thus providing novel targeted therapeutic strategies for tauopathies.

Language: Английский

Citations

11
Liquid-liquid phase separation in subcellular assemblages and signaling pathways: Chromatin modifications induced gene regulation for cellular physiology and functions including carcinogenesis DOI

Subhajit Chakraborty,

Jagdish Mishra,

Ankan Roy

et al.

Biochimie, Journal Year: 2024, Volume and Issue: 223, P. 74 - 97

Published: May 7, 2024

Language: Английский

Citations

4