Impact of Phosphorylation on the Structural Ensemble of alpha-Synuclein in Aqueous Solution DOI Open Access
Emile De Bruyn, Anton Emil Dorn, Giulia Rossetti

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: March 12, 2023

Abstract Serine 129 can be phosphorylated in pathological inclusions formed by the intrinsically disordered protein human α -synuclein (AS), a key player Parkinson’s disease and other synucleinopathies. Here, molecular simulations provide insight into structural ensemble of AS. The suggest that phosphorylation does not impact content physiological AS conformational aqueous solution, as phosphate group is mostly solvated. hydrophobic region contains β -hairpin structures, which may increase propensity to undergo amyloid formation, seen non-physiological (non-acetylated) form recent simulation study. Our findings are consistent with existing experimental data, caveat observed limitations force field for moiety. Figure

Language: Английский

Acute lipid droplet accumulation induced by the inhibition of the phospholipase DDHD2 does not affect the level, solubility, or phosphoserine-129 status of α-synuclein DOI
Magdalena M. Bolsinger, Tim E. Moors,

Lisa Brontesi

et al.

Metabolic Brain Disease, Journal Year: 2025, Volume and Issue: 40(1)

Published: Jan. 24, 2025

Language: Английский

Citations

0
Bridging the gap: investigating the role of phosphorylation at the serine 129 site of α-synuclein in VAPB-PTPIP51 interactions DOI Creative Commons
Weijin Liu,

Yongquan Lu,

Jia Liu

et al.

Acta Neuropathologica Communications, Journal Year: 2025, Volume and Issue: 13(1)

Published: Feb. 24, 2025

Parkinson's Disease (PD) is characterized by the aggregation and accumulation of α-synuclein (α-syn), along with abnormally high levels α-syn phosphorylation at serine 129 site (pSer α-syn, p-α-syn). However, mechanisms underlying extensive in pathogenesis PD, as well role p-α-syn process, remain unclear. Furthermore, though could bind to VAPB loosen Endoplasmic Reticulum (ER)-mitochondria associations disrupting VAPB-PTPIP51 tethers, whether how regulates interactions, remains Herein, Co-Immunoprecipitation Mass Spectrometry (CO-IP/MS) studies were preformed identify compare Protein-Protein Interactions (PPIs) phosphorylated total midbrains Thy1-SNCA transgenic mice. We further performed CO-IP Molecular Dynamics (MD) simulation assays confirm influence on aforementioned interactions. Additionally, we Gene Ontology (GO) Kyoto Encyclopedia Genes Genomes (KEGG) analyses annotate functional features common interacting proteins VAPB. The potential downstream verified via CO-IP. According MD results, increased interacted directly PTPIP51. pathway enrichment revealed that significantly involved protein binding, metal ion structural constituent cytoskeleton, intermediate filament microtubule organization processes. Moreover, our findings confirmed interactions target (CLTC, CAMK2A, ATP1A3, TUBB4B) These collectively elucidate underpinnings interaction between both hope these will provide valuable insights into regulatory pertinent diseases.

Language: Английский

Citations

0
A personalised and comprehensive approach is required to suppress or replenish SNCA for Parkinson’s disease DOI Creative Commons
Dunhui Li, Wai Yan Yau,

Shengdi Chen

et al.

npj Parkinson s Disease, Journal Year: 2025, Volume and Issue: 11(1)

Published: March 4, 2025

Based on the prevailing α-synuclein "gain-of-function" hypothesis, reducing levels and removing its aggregates is a current focus of disease-modifying therapies for Parkinson's disease. Emerging evidence "loss-of-function" suggests that it may be necessary to replenish monomeric levels. We propose personalized comprehensive approach different subgroups based whether likely contribute disease pathogenesis through "gain-of-function", "loss-of-function", or both mechanisms.

Language: Английский

Citations

0
Serine-129 phosphorylated α-synuclein drives mitochondrial dysfunction and calcium dysregulation in Parkinson’s disease model DOI Creative Commons
Jie Jiao, Weijin Liu, Ge Gao

et al.

Frontiers in Aging Neuroscience, Journal Year: 2025, Volume and Issue: 17

Published: March 31, 2025

Phosphorylation of α -synuclein at serine-129 (p- -syn) is a hallmark Parkinson’s disease (PD) and constitutes nearly 90% α-synuclein in Lewy bodies, playing critical role progression. Despite its pathological significance, the molecular targets mechanisms driving p- -syn-induced toxicity, particularly mitochondrial dysfunction, remain poorly understood. In this study, we observed dysfunction primary cortical neurons derived from mice overexpressing human (h- -syn), which also exhibit elevated levels -syn. Notably, inhibiting Ser129 phosphorylation improved function, underscoring -syn damage. To investigate mechanism, performed co-immunoprecipitation (CO-IP) combined with mass spectrometry (MS) to identify binding proteins. This analysis identified protein tyrosine phosphatase interacting 51 (PTPIP51) vesicle-associated membrane protein-associated B (VAPB) as key partners. Both proteins are localized mitochondria-associated endoplasmic reticulum mem-brane (MAM) essential for calcium transfer between (ER) mitochondria. Our results showed that binds PTPIP51 VAPB, disrupting signaling ER Importantly, inhibition partially rescued homeostasis. These findings uncover novel mechanism by drives dysregulation through interactions MAM-associated proteins, providing new insights into PD pathogenesis potential therapeutic targets.

Language: Английский

Citations

0
α-Synuclein seeding amplification assays for diagnosing synucleinopathies: an innovative tool in clinical implementation DOI Creative Commons
Yaoyun Kuang, Hengxu Mao, Xiaoyun Huang

et al.

Translational Neurodegeneration, Journal Year: 2024, Volume and Issue: 13(1)

Published: Nov. 21, 2024

Abstract The spectrum of synucleinopathies, including Parkinson’s disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), is characterized by α-synuclein (αSyn) pathology, which serves as the definitive diagnostic marker. However, current methods primarily rely on motor symptoms that manifest years after initial neuropathological changes, thereby delaying potential treatment. symptomatic overlap between PD MSA further complicates diagnosis, highlighting need for precise differential these overlapping neurodegenerative diseases. αSyn misfolding aggregation occur before clinical appear, suggesting detection pathological could enable early molecular diagnosis synucleinopathies. Recent advances in seed amplification assay (SAA) offer a tool detecting diseases identifying fluid tissue samples, even at preclinical stages. Extensive research has validated effectiveness reproducibility SAAs diagnosing ongoing efforts focusing optimizing conditions more accessible samples specific species to differentiate various This review offers thorough overview SAA technology, exploring its applications addressing challenges, outlining future directions use.

Language: Английский

Citations

2
Impact of Phosphorylation on the Physiological Form of Human alpha-Synuclein in Aqueous Solution DOI Creative Commons
Emile De Bruyn, Anton Emil Dorn, Giulia Rossetti

et al.

Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: 64(21), P. 8215 - 8226

Published: Oct. 28, 2024

Serine 129 can be phosphorylated in pathological inclusions formed by the intrinsically disordered protein human α-synuclein (AS), a key player Parkinson's disease and other synucleinopathies. Here, molecular simulations provide insight into structural ensemble of AS. The allow us to suggest that phosphorylation significantly impacts content physiological AS conformational aqueous solution, as phosphate group is mostly solvated. hydrophobic region contains β-hairpin structures, which may increase propensity undergo amyloid formation, seen nonphysiological (nonacetylated) form recent simulation study. Our findings are consistent with existing experimental data caveat observed limitations force field for moiety.

Language: Английский

Citations

1
Harnessing Natural Inhibitors of Protein Synthesis for Cancer Therapy: A Comprehensive Review DOI Creative Commons
Liqin Liu, Zhihui Li, Wenshuang Wu

et al.

Pharmacological Research, Journal Year: 2024, Volume and Issue: 209, P. 107449 - 107449

Published: Oct. 4, 2024

Cancer treatment remains a formidable challenge in modern medicine, necessitating nuanced understanding of its molecular underpinnings and the identification novel therapeutic modalities. Among intricate web cellular pathways implicated oncogenesis, protein synthesis has emerged as fundamental process warranting meticulous investigation. This review elucidates multifaceted role tumor initiation progression, highlighting potential targeting key nodes within these viable strategies. Natural products have long served source bioactive compounds with owing to their structural diversity evolutionary honing. Within this framework, we provide thorough examination natural inhibitors promising candidates for cancer therapy, drawing upon recent advancements mechanistic insights. By synthesizing current evidence elucidating challenges opportunities, aims galvanize further research into development product-based anticancer therapeutics, thereby advancing clinical armamentarium against malignancies.

Language: Английский

Citations

0
Impact of Phosphorylation on the Structural Ensemble of alpha-Synuclein in Aqueous Solution DOI Open Access
Emile De Bruyn, Anton Emil Dorn, Giulia Rossetti

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: March 12, 2023

Abstract Serine 129 can be phosphorylated in pathological inclusions formed by the intrinsically disordered protein human α -synuclein (AS), a key player Parkinson’s disease and other synucleinopathies. Here, molecular simulations provide insight into structural ensemble of AS. The suggest that phosphorylation does not impact content physiological AS conformational aqueous solution, as phosphate group is mostly solvated. hydrophobic region contains β -hairpin structures, which may increase propensity to undergo amyloid formation, seen non-physiological (non-acetylated) form recent simulation study. Our findings are consistent with existing experimental data, caveat observed limitations force field for moiety. Figure

Language: Английский

Citations

0