Single‐Molecule Insight Into α‐Synuclein Fibril Structure and Mechanics Modulated by Chemical Compounds DOI Creative Commons
Xiang Li, Lulu Bi, Shenqing Zhang

et al.

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

Published: Feb. 14, 2025

α-Syn fibrils, a key pathological hallmark of Parkinson's disease, is closely associated with disease initiation and progression. Several small molecules are found to bind or dissolve α-syn offering potential therapeutic applications. Here, an innovative optical tweezers-based, fluorescence-combined approach developed probe the mechanical characteristics fibrils at single-molecule level. When subjected axial stretching, local deformation within appeared forces above 50 pN. These structural alternations occurred stepwise irreversible, suggesting unfolding individual subdomains. Additionally, exhibits high heterogeneity in lateral disruption, rupture force ranging from 500 The impact different compounds on structure features further examined. Notably, epigallocatechin gallate (EGCG) generally attenuates by wedging into N-terminal polar groove induces fibril dissociation. Conversely, copper chlorophyllin A (CCA) attaches four sites wrapping around core, reinforcing stability against forces. work offers effective method for characterizing single-fibril properties bridges compound-induced response. insights valuable understanding amyloid mechanics their regulation molecules.

Language: Английский

Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets DOI Creative Commons
Chao Gao, Jingwen Jiang, Yuyan Tan

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Sept. 22, 2023

Abstract Microglia activation is observed in various neurodegenerative diseases. Recent advances single-cell technologies have revealed that these reactive microglia were with high spatial and temporal heterogeneity. Some identified specific states correlate pathological hallmarks are associated functions. both exert protective function by phagocytosing clearing protein aggregates play detrimental roles due to excessive uptake of aggregates, which would lead microglial phagocytic ability impairment, neuroinflammation, eventually neurodegeneration. In addition, peripheral immune cells infiltration shapes into a pro-inflammatory phenotype accelerates disease progression. also act as mobile vehicle propagate aggregates. Extracellular vesicles released from autophagy impairment all contribute progression Thus, enhancing phagocytosis, reducing microglial-mediated inhibiting exosome synthesis secretion, promoting conversion considered be promising strategies for the therapy Here we comprehensively review biology diseases, including Alzheimer’s disease, Parkinson’s multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, dementia Lewy bodies Huntington’s disease. We summarize possible microglia-targeted interventions treatments against diseases preclinical clinical evidence cell experiments, animal studies, trials.

Language: Английский

Citations

418
A biological definition of neuronal α-synuclein disease: towards an integrated staging system for research DOI
Tanya Simuni, Lana M. Chahine, Kathleen L. Poston

et al.

The Lancet Neurology, Journal Year: 2024, Volume and Issue: 23(2), P. 178 - 190

Published: Jan. 22, 2024

Language: Английский

Citations

236
NADPH Oxidases: From Molecular Mechanisms to Current Inhibitors DOI Creative Commons
Alessandra Cipriano, Monica Viviano, Alessandra Feoli

et al.

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(17), P. 11632 - 11655

Published: Aug. 31, 2023

NADPH oxidases (NOXs) form a family of electron-transporting membrane enzymes whose main function is reactive oxygen species (ROS) generation. Strong evidence suggests that ROS produced by NOX are major contributors to oxidative damage under pathologic conditions. Therefore, blocking the undesirable actions these therapeutic strategy for treating various pathological disorders, such as cardiovascular diseases, inflammation, and cancer. To date, identification selective inhibitors quite challenging, precluding pharmacologic demonstration targets in vivo. The aim this Perspective furnish an updated outlook about small-molecule described over last two decades. Structures, activities, vitro/in vivo specificity discussed, well biological assays used.

Language: Английский

Citations

56
Shining New Light on Biological Systems: Luminescent Transition Metal Complexes for Bioimaging and Biosensing Applications DOI Creative Commons
Lawrence Cho‐Cheung Lee, Kenneth Kam‐Wing Lo

Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(15), P. 8825 - 9014

Published: July 25, 2024

Luminescence imaging is a powerful and versatile technique for investigating cell physiology pathology in living systems, making significant contributions to life science research clinical diagnosis. In recent years, luminescent transition metal complexes have gained attention diagnostic therapeutic applications due their unique photophysical photochemical properties. this Review, we provide comprehensive overview of the development bioimaging biosensing applications, with focus on centers d

Language: Английский

Citations

41
Prasinezumab slows motor progression in rapidly progressing early-stage Parkinson’s disease DOI Creative Commons
Gennaro Pagano, Kirsten I. Taylor,

Judith Anzures Cabrera

et al.

Nature Medicine, Journal Year: 2024, Volume and Issue: 30(4), P. 1096 - 1103

Published: April 1, 2024

Abstract Prasinezumab, a monoclonal antibody that binds aggregated α-synuclein, is being investigated as potential disease-modifying therapy in early-stage Parkinson’s disease. Although the PASADENA phase 2 study, primary endpoint (Movement Disorder Society Unified Disease Rating Scale (MDS-UPDRS) sum of Parts I + II III) was not met, prasinezumab-treated individuals exhibited slower progression motor signs than placebo-treated participants (MDS-UPDRS Part III). We report here an exploratory analysis assessing whether prasinezumab showed greater benefits on prespecified subgroups with faster progression. Prasinezumab’s effects disease were assessed four and six subpopulations PASADENA: use monoamine oxidase B inhibitors at baseline (yes versus no); Hoehn Yahr stage (2 1); rapid eye movement sleep behavior disorder data-driven subphenotypes (diffuse malignant nondiffuse malignant); age (≥60 years <60 years); sex (male female); duration (>12 months <12 months); diagnosis (akinetic–rigid tremor-dominant); (postural instability gait dysfunction tremor-dominant). In these subpopulations, effect slowing rapidly progressing (for example, who diffuse or taking baseline). This suggests that, trial 1-year duration, might reduce to extent more However, because this post hoc analysis, additional randomized clinical trials are needed validate findings.

Language: Английский

Citations

39
Evolving Landscape of Parkinson’s Disease Research: Challenges and Perspectives DOI Creative Commons
Rumiana Koynova, Janet M. Sasso, Qiongqiong Angela Zhou

et al.

ACS Omega, Journal Year: 2025, Volume and Issue: 10(2), P. 1864 - 1892

Published: Jan. 8, 2025

Parkinson's disease (PD) is a progressive neurodegenerative disorder that primarily affects movement. It occurs due to gradual deficit of dopamine-producing brain cells, particularly in the substantia nigra. The precise etiology PD not fully understood, but it likely involves combination genetic and environmental factors. therapies available at present alleviate symptoms do stop disease's advancement. Research endeavors are currently directed inventing disease-controlling aim inherent mechanisms PD. biomarker breakthroughs hold enormous potential: earlier diagnosis, better monitoring, targeted treatment based on individual response could significantly improve patient outcomes ease burden this disease. research an active evolving field, focusing understanding mechanisms, identifying biomarkers, developing new treatments, improving care. In report, we explore data from CAS Content Collection outline progress We analyze publication landscape offer perspective into latest expertise advancements. Key emerging concepts reviewed strategies fight evaluated. Pharmacological targets, risk factors, as well comorbid diseases explored, clinical usage products against with their production pipelines trials for drug repurposing examined. This review aims comprehensive overview advancing current about PD, define challenges, assess growth prospects stimulate efforts battling

Language: Английский

Citations

2
Quantum-mechanics-based structural analysis of phenolic glycosides from Cuscuta japonica seeds with protective effects against H2O2-induced oxidative stress in SH-SY5Y cells DOI

Hau Thi Hong Bui,

Ajay Uprety, Trung Huy Ngo

et al.

Phytochemistry, Journal Year: 2025, Volume and Issue: unknown, P. 114420 - 114420

Published: Jan. 1, 2025

Language: Английский

Citations

2
An update on pathogenesis and clinical scenario for Parkinson’s disease: diagnosis and treatment DOI Open Access

Hussaini Adam,

Subash C. B. Gopinath, M. K. Md Arshad

et al.

3 Biotech, Journal Year: 2023, Volume and Issue: 13(5)

Published: April 27, 2023

Language: Английский

Citations

24
Alpha-Synuclein Contribution to Neuronal and Glial Damage in Parkinson’s Disease DOI Open Access
Kamil Saramowicz, Natalia Siwecka, Grzegorz Galita

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 25(1), P. 360 - 360

Published: Dec. 26, 2023

Parkinson’s disease (PD) is a complex neurodegenerative characterized by the progressive loss of dopaminergic neurons in substantia nigra and widespread accumulation alpha-synuclein (αSyn) protein aggregates. αSyn aggregation disrupts critical cellular processes, including synaptic function, mitochondrial integrity, proteostasis, which culminate neuronal cell death. Importantly, pathology extends beyond neurons—it also encompasses spreading throughout environment internalization microglia astrocytes. Once internalized, glia can act as neuroprotective scavengers, limit spread αSyn. However, they become reactive, thereby contributing to neuroinflammation progression PD. Recent advances research have enabled molecular diagnosis PD accelerated development targeted therapies. Nevertheless, despite more than two decades research, mechanisms, induction damage remain incompletely understood. Unraveling interplay between αSyn, neurons, may provide insights into initiation progression, bring us closer exploring new effective therapeutic strategies. Herein, we an overview recent studies emphasizing multifaceted nature its impact on both neuron glial damage.

Language: Английский

Citations

22
Effect of chemically synthesized psilocybin and psychedelic mushroom extract on molecular and metabolic profiles in mouse brain DOI Creative Commons

Orr Shahar,

Alexander Botvinnik,

Amit Shwartz

et al.

Molecular Psychiatry, Journal Year: 2024, Volume and Issue: 29(7), P. 2059 - 2073

Published: Feb. 20, 2024

Psilocybin, a naturally occurring, tryptamine alkaloid prodrug, is currently being investigated for the treatment of range psychiatric disorders. Preclinical reports suggest that biological effects psilocybin-containing mushroom extract or "full spectrum" (psychedelic) (PME), may differ from those chemically synthesized psilocybin (PSIL). We compared PME to PSIL on head twitch response (HTR), neuroplasticity-related synaptic proteins and frontal cortex metabolomic profiles in male C57Bl/6j mice. HTR measurement showed similar over 20 min. Brain specimens (frontal cortex, hippocampus, amygdala, striatum) were assayed proteins, GAP43, PSD95, synaptophysin SV2A, using western blots. These serve as indicators plasticity. Three days after treatment, there was minimal increase proteins. After 11 days, significantly increased GAP43 (p = 0.019; p 0.039 respectively) hippocampus 0.015; 0.027) 0.041; 0.05) amygdala 0.035; 0.004). SV2A 0.036) did so 0.014). In striatum, by only 0.023). There no significant PSD95 any brain area when these analyzed separately. Nested analysis variance (ANOVA) each 4 all areas versus vehicle control, while observed limited SV2A. Metabolomic analyses pre-frontal performed untargeted polar metabolomics utilizing capillary electrophoresis - Fourier transform mass spectrometry (CE-FTMS) differential metabolic separation between groups. The purines guanosine, hypoxanthine inosine, associated with oxidative stress energy production pathways, progressive decline VEH PME. conclusion, our protein findings has more potent prolonged effect plasticity than PSIL. Our data support gradient inert via chemical further supporting effects. Further studies are needed confirm extend identify molecules be responsible enhanced alone.

Language: Английский

Citations

15