C9orf72-linked arginine-rich dipeptide repeats aggravate pathological phase separation of G3BP1 DOI Creative Commons
Margot Van Nerom, Junaid Ahmed, Tamás Lázár

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(50)

Published: Dec. 2, 2024

The toxic effects of C9orf72-derived arginine-rich dipeptide repeats (R-DPRs) on cellular stress granules in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia remain unclear at the molecular level. Stress are formed through switch Ras GTPase-activating protein-binding protein 1 (G3BP1) by RNA from a closed inactive state to an open activated state, driving formation organelle liquid–liquid phase separation (LLPS). We show that R-DPRs bind G3BP1 thousand times stronger than initiate LLPS much more effectively. Their pathogenic effect is underscored slow transition R-DPR–G3BP1 droplets aggregated, ThS-positive states can recruit ALS-linked proteins hnRNPA1, hnRNPA2, TDP-43. Deletion constructs simulations R-DPR binding mediated via negatively charged intrinsically disordered region (IDR1) protein, allosterically regulated its positively IDR3. Bioinformatic analyses point strong mechanistic parallels these with interaction nucleolar nucleophosmin (NPM1) underscore interact many other similar stress-granule proteins, extending underlying mechanism toxicity cells. Our results also highlight characteristic differences between two R-DPRs, poly-GR poly-PR, suggest primary pathological target not NPM1 nucleoli, but affected

Language: Английский

Biological importance of arginine: A comprehensive review of the roles in structure, disorder, and functionality of peptides and proteins DOI
Munishwar N. Gupta, Vladimir N. Uversky

International Journal of Biological Macromolecules, Journal Year: 2023, Volume and Issue: 257, P. 128646 - 128646

Published: Dec. 6, 2023

Language: Английский

Citations

33
Friend or foe: The role of stress granule in neurodegenerative disease DOI

Qinqin Cui,

Zhongyi Liu,

Ge Bai

et al.

Neuron, Journal Year: 2024, Volume and Issue: 112(15), P. 2464 - 2485

Published: May 13, 2024

Language: Английский

Citations

12
Biomolecular condensates in immune cell fate DOI
Srikanth Kodali, Caroline M. Sands, Lei Guo

et al.

Nature reviews. Immunology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 28, 2025

Language: Английский

Citations

1
Perillaldehyde Improves Parkinson‐Like Deficits by Targeting G3BP Mediated Stress Granule Assembly in Preclinical Models DOI Creative Commons

Minglv Fang,

Lingling Luo,

Youjia Chen

et al.

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 14, 2025

Abstract Stress granules (SGs) fulfill a pivotal role in host defense mechanisms, by sequestering both mRNA and protein via the process of liquid–liquid phase separation (LLPS). In this study, we showed that perillaldehyde (PAE), natural occurring compound, bound directly to core SGs, Ras GTPase‐activating protein‐binding 1/2 (G3BP1/2), thereby inducing assembly SGs through LLPS G3BP/RNA complexes vitro. Moreover, Parkinson's disease (PD) models using Caenorhabditis elegans ( C. ) mice, PAE administration prompted SG formation, enhanced eIF2α phosphorylation, shielded dopaminergic neurons from toxic insults, mitigated α‐synuclein (α‐syn) aggregation, improved PD‐like motor disorders. addition, these findings revealed interaction between G3BP1 histone deacetylase 6 (HDAC6) inhibited functions cytoplasmic HDAC6 reduced α‐syn aggregation cells worms. Notably, inhibition gtbp‐1 tiar‐1 RNAi effectively counteracted beneficial effects . Collectively, results imply may exert neuroprotective targeting G3BP‐mediated safeguarding damage.

Language: Английский

Citations

1
ALS’ Perfect Storm: C9orf72-Associated Toxic Dipeptide Repeats as Potential Multipotent Disruptors of Protein Homeostasis DOI Creative Commons

Paulien H. Smeele,

Giuliana Cesare, Thomas Vaccari

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(2), P. 178 - 178

Published: Jan. 17, 2024

Protein homeostasis is essential for neuron longevity, requiring a balanced regulation between protein synthesis and degradation. The clearance of misfolded aggregated proteins, mediated by autophagy the ubiquitin–proteasome systems, maintains in neurons, which are post-mitotic thus cannot use cell division to diminish burden proteins. When pathways overwhelmed or otherwise disrupted, accumulation proteins can lead activation ER stress formation granules, predominantly attempt restore suppressing global translation. Alterations these processes have been widely reported among studies investigating toxic function dipeptide repeats (DPRs) produced G4C2 expansion C9orf72 gene patients with amyotrophic lateral sclerosis (ALS) frontotemporal dementia (FTD). In this review, we outline modalities DPR-induced disruptions observed wide range models C9orf72-linked ALS/FTD. We also discuss relative importance each DPR toxicity, possible synergies DPRs, functional relevance aggregation disease pathogenesis. Finally, highlight interdependencies effects reflect on feedback feedforward mechanisms their contribution progression. A better understanding DPR-associated pathogenesis discussed review might shed light vulnerabilities that may be amenable therapeutic interventions.

Language: Английский

Citations

5
Late gestational exposure to fenvalerate impacts ovarian reserve in neonatal mice via YTHDF2-mediated P-body assembly DOI

Fei He,

Xinyi Mu, Yan Zhang

et al.

The Science of The Total Environment, Journal Year: 2024, Volume and Issue: 925, P. 171790 - 171790

Published: March 18, 2024

Language: Английский

Citations

5
The complex roles of m6A modifications in neural stem cell proliferation, differentiation, and self-renewal and implications for memory and neurodegenerative diseases DOI Creative Commons

LI Yan-xi,

Jing Xue,

Yuejia Ma

et al.

Neural Regeneration Research, Journal Year: 2024, Volume and Issue: 20(6), P. 1582 - 1598

Published: June 3, 2024

N6-methyladenosine (m 6 A), the most prevalent and conserved RNA modification in eukaryotic cells, profoundly influences virtually all aspects of mRNA metabolism. plays crucial roles neural stem cell genesis regeneration, where it is highly concentrated actively involved these processes. Changes m A levels expression related enzymatic proteins can lead to neurological dysfunction contribute development diseases. Furthermore, proliferation differentiation as well nerve are intimately linked memory function neurodegenerative This paper presents a comprehensive review proliferation, differentiation, self-renewal, its implications has demonstrated divergent effects on cells. These observed contradictions may arise from time-specific nature differential impact cells across various stages development. Similarly, diverse distinct types could be attributed involvement specific brain regions formation recall. Inconsistencies different models disease, particularly Alzheimer's disease Parkinson's suggest that disparities variations affected regions. Notably, opposing changes exposed manganese compared normal further underscore complexity A's role The diseases, appear contradictory. inconsistencies varying environments.

Language: Английский

Citations

4
Targeting m6A mRNA demethylase FTO alleviates manganese-induced cognitive memory deficits in mice DOI
Yi Wen,

Zhushan Fu,

Jiashuo Li

et al.

Journal of Hazardous Materials, Journal Year: 2024, Volume and Issue: 476, P. 134969 - 134969

Published: June 18, 2024

Language: Английский

Citations

4
Regulation of physiological and pathological condensates by molecular chaperones DOI Creative Commons

Nadeen Akaree,

Valentina Secco,

Flonia Levy‐Adam

et al.

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

Published: Jan. 5, 2025

Biomolecular condensates are dynamic membraneless compartments that regulate a myriad of cellular functions. A particular type physiological condensate called stress granules (SGs) has gained increasing interest due to its role in the response and various diseases. SGs, composed several hundred RNA‐binding proteins, form transiently protect mRNAs from translation disassemble when subsides. Interestingly, SGs contain aggregation‐prone such as TDP‐43, FUS, hnRNPA1, others, which typically found pathological inclusions seen autopsy tissues amyotrophic lateral sclerosis (ALS) frontotemporal dementia (FTD) patients. Moreover, mutations these genes lead familial ALS FTD. This led researchers propose aggregation is seeded by aberrant SGs: fail properly disassemble, lose their properties, become finally ‘mature’ into aggregates. Here, we discuss evidence supporting this model for ALS/FTD‐associated proteins. We further continue focus on molecular chaperone‐mediated regulation one hand, other. In addition review ALS/FTD‐relevant nuclear condensates, namely paraspeckles, anisosomes, nucleolar amyloid bodies, emerging chaperones. As majority chaperoning mechanisms disassembly, highlight parallel themes condensation across different chaperone families, underscoring potential early disease intervention.

Language: Английский

Citations

0
Therapeutic potential of natural products in stress granules: underlying molecular mechanisms and future perspectives DOI Creative Commons

Huancai Fan,

Chunhua Wang, Sijin Liu

et al.

Current Pharmaceutical Analysis, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

Citations

0