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

Loss of monomeric alpha-synuclein (synucleinopenia) and the origin of Parkinson's disease DOI Creative Commons
Alberto J. Espay,

Andrew Lees

Parkinsonism & Related Disorders, Journal Year: 2024, Volume and Issue: 122, P. 106077 - 106077

Published: March 3, 2024

These facts argue against the gain-of-function synucleinopathy hypothesis, which proposes that Lewy pathology causes Parkinson's disease: (1) most brains from people without neurological symptoms have multiple pathologies; (2) neither type nor distribution correlate with disease severity or progression in disease; (3) aggregated α-synuclein form of bodies is not a space-occupying lesion but insoluble fraction its precursor, soluble monomeric α-synuclein; (4) spread passive, occurring by irreversible nucleation, active replication; and (5) low cerebrospinal fluid levels predict brain atrophy clinical progression. The transformation into may occur as response to biological, toxic, infectious stressors whose persistence perpetuates nucleation process, depleting normal eventually leading neuronal death. We propose testing loss-of-function synucleinopenia hypothesis evaluating neurodegenerative rescue effect replenishing α-synuclein.

Language: Английский

Citations

17
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

16
Nicotinic Acetylcholine Receptors in Glial Cells as Molecular Target for Parkinson’s Disease DOI Creative Commons
Érica Novaes Soares, Ana Carla dos Santos Costa,

Gabriel de Jesus Ferrolho

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(6), P. 474 - 474

Published: March 7, 2024

Parkinson’s disease (PD) is a progressive neurodegenerative characterized by resting tremor, bradykinesia, rigidity, and postural instability that also includes non-motor symptoms such as mood dysregulation. Dopamine (DA) the primary neurotransmitter involved in this disease, but cholinergic imbalance has been implicated. Current intervention PD focused on replenishing central DA, which provides remarkable temporary symptomatic relief does not address neuronal loss progression of disease. It well established nicotinic receptors (nAChRs) can regulate DA release nicotine itself may have neuroprotective effects. Recent studies identified nAChRs nonneuronal cell types, including glial cells, where they inflammatory responses. Given crucial role neuroinflammation dopaminergic degeneration involvement microglia astrocytes response, provide novel therapeutic target prevention and/or treatment PD. In review, following brief discussion PD, we focus cells and, specifically, their pathology treatment.

Language: Английский

Citations

11
Physiological roles of α-synuclein serine-129 phosphorylation – not an oxymoron DOI
Nagendran Ramalingam, Christian Haass, Ulf Dettmer

et al.

Trends in Neurosciences, Journal Year: 2024, Volume and Issue: 47(7), P. 480 - 490

Published: June 12, 2024

Language: Английский

Citations

10
Experimental Evidence for Phosphorylation-Driven Allosteric Regulation of Alpha Synuclein Function DOI Creative Commons

Ashlyn N. Dollar,

Ian Webb

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

Published: Feb. 26, 2025

Phosphorylation of serine 129 (pS129) in the intrinsically disordered protein alpha synuclein has long been associated with neurodegenerative disease. In past several years, functional relevance pS219 uncovered by electrophysiology, immunoprecipitation, and proteomics as intricately connected neurotransmitter release synaptic vesicle (SV) cycling. Unexpectedly, binding to SNARE complex proteins VAMP-2 synapsin only occurs phosphorylation-competent synuclein. The domain shown be residues 96-110, which does not include phosphorylated residue, hinting at allosteric regulation protein-protein interactions pS129. Within this study, cross-linking, covalent labeling, collision induced unfolding pS129 - well an additional encountered form brain, oxidized-M1, M5, M116, M127 are studied utilizing tandem mass spectrometry. Collision gives a fingerprint structures' relative compactness stabilities various conformations. Covalent labeling identifies solvent accessible reveals hydrophobicity (or hydrophilicity) their microenvironment, while cross-linking maps proximity residue pairs. combination unfolding, show unequivocally that phosphorylated-S129 results more stable, compact form. Our provide evidence extensively folded amphipathic region interacts strongly domain. phosphorylation-induced folding likely tunes other SVs membranes.

Language: Английский

Citations

1
Biomimetic Nanoparticles Enhance Recovery of Movement Disorders in Parkinson’s Disease by Improving Microglial Mitochondrial Homeostasis and Suppressing Neuroinflammation DOI
Liang Li,

Chunbin Sun,

Shanglin Cai

et al.

ACS Applied Materials & Interfaces, Journal Year: 2025, Volume and Issue: unknown

Published: April 9, 2025

Neuroinflammation is a key risk factor for cognitive impairment, and microglia are the main drivers. Metformin has been shown to suppress inflammation reduce microglial activation, protecting neurons from damage. However, its clinical efficacy limited by low bioavailability metabolic challenges, especially in terms of precise delivery specific targets. To overcome this problem, we developed biomimetic nanoparticles (MePN@BM) enhance targeted metformin. Through homologous targeting, efficiency drugs inflammatory site Parkinson's disease was enhanced improve therapeutic effect. The results showed that MePN@BM effectively delivers metformin brain, promotes autophagy, restores mitochondrial membrane potential, reduces oxidative stress. In (PD) mouse model, improved motor function, repaired dopaminergic neurons, cleared α-synuclein aggregates. Notably, transcriptome analysis revealed enriched inflammation-related pathways, immunofluorescence PD mice treated with had higher levels anti-inflammatory factors lower pro-inflammatory factors. Therefore, it provides promising strategy treatment inflammation-mediated dysfunction.

Language: Английский

Citations

1
Live-cell quantification reveals viscoelastic regulation of synapsin condensates by α-synuclein DOI Creative Commons
Huan Wang, Christian Hoffmann, Johannes Vincent Tromm

et al.

Science Advances, Journal Year: 2025, Volume and Issue: 11(16)

Published: April 18, 2025

Synapsin and α-synuclein represent a growing list of condensate-forming proteins where the material states condensates are directly linked to cellular functions (e.g., neurotransmission) pathology neurodegeneration). However, quantifying condensate properties in living systems has been substantial challenge. Here, we develop micropipette aspiration whole-cell patch-clamp (MAPAC), platform that allows direct quantification live cells. We find 10,000-fold variations viscoelasticity synapsin condensates, regulated by partitioning α-synuclein, marker for synucleinopathies. Through vitro reconstitutions, identify multiple molecular factors distinctly regulate viscosity, interfacial tension, maturation confirming roles α-synuclein. Overall, our study provides unprecedented quantitative insights into neuronal reveals crucial role regulating viscoelasticity. Furthermore, envision MAPAC applicable broad range vivo.

Language: Английский

Citations

1
Gut–Brain Axis in Focus: Polyphenols, Microbiota, and Their Influence on α-Synuclein in Parkinson’s Disease DOI Open Access

Elizabeth Riegelman,

Kathy S. Xue, Jia-Sheng Wang

et al.

Nutrients, Journal Year: 2024, Volume and Issue: 16(13), P. 2041 - 2041

Published: June 27, 2024

With the recognition of importance gut-brain axis in Parkinson's disease (PD) etiology, there is increased interest developing therapeutic strategies that target α-synuclein, hallmark abhorrent protein PD pathogenesis, which may originate gut. Research has demonstrated inhibiting aggregation, oligomerization, and fibrillation α-synuclein are key for modification. Polyphenols, rich fruits vegetables, drawing attention their potential role this context. In paper, we reviewed how polyphenols influence composition functional capabilities gut microbiota resulting microbial metabolites potentially enhance modulation aggregation. Understanding interaction between identifying specific microbes efficacy crucial precision nutrition based on microbiome.

Language: Английский

Citations

9
Research Priorities on the Role of α‐Synuclein in Parkinson's Disease Pathogenesis DOI Creative Commons
Jacqueline Burré, Robert H. Edwards, Glenda M. Halliday

et al.

Movement Disorders, Journal Year: 2024, Volume and Issue: 39(10), P. 1663 - 1678

Published: June 30, 2024

Abstract Various forms of Parkinson's disease, including its common sporadic form, are characterized by prominent α‐synuclein (αSyn) aggregation in affected brain regions. However, the role αSyn pathogenesis and evolution disease remains unclear, despite vast research efforts more than a quarter century. A better understanding αSyn, either primary or secondary, is critical for developing disease‐modifying therapies. Previous attempts to hone this have been challenged experimental limitations, but recent technological advances may facilitate progress. The Scientific Issues Committee International Parkinson Movement Disorder Society (MDS) charged panel experts field discuss current scientific priorities identify strategies with potential breakthrough. © 2024 Author(s). Disorders published Wiley Periodicals LLC on behalf Society.

Language: Английский

Citations

9
Curcumin as a potential therapeutic agent for treating neurodegenerative diseases DOI Creative Commons

Valeria Perales-Salinas,

Sushmitha S. Purushotham,

Yossi Buskila

et al.

Neurochemistry International, Journal Year: 2024, Volume and Issue: 178, P. 105790 - 105790

Published: June 7, 2024

Neurodegenerative diseases are characterized by the progressive loss of neuronal structure and function, posing a tremendous burden on health systems worldwide. Although underlying pathological mechanisms for various neurodegenerative still unclear, common hallmark is abundance neuroinflammatory processes, which affect both disease onset progression. In this review, we explore pathways role neuroinflammation in further assess potential use curcumin, natural spice with antioxidant anti-inflammatory properties that has been extensively used worldwide as traditional medicine therapeutic agent. Following examination preclinical clinical studies assessed curcumin agent, highlight bioavailability body discuss challenges benefits using compound treating neurodegeneration. elucidating involvement aging neurodegeneration great developing future CNS-related targets, research required to elucidate Curcumin affects brain physiology, especially BBB integrity, under physiological conditions.

Language: Английский

Citations

8