Effect of Electric Field on α-Synuclein Fibrils: Revealed by Molecular Dynamics Simulations DOI Open Access
Jamoliddin Razzokov, Sunnatullo Fazliev,

Mukhriddin Makhkamov

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(7), P. 6312 - 6312

Published: March 28, 2023

The self-association of amylogenic proteins to the fibril form is considered a pivotal factor in pathogenesis neurodegenerative diseases, including Parkinson's disease (PD). PD causes unintended or uncontrollable movements its common symptoms. α-synuclein major cause development and thus has been main target numerous studies suppress sequester expression effectively degrade it. Nonetheless, date, there are no efficient proven ways prevent pathological protein aggregation. Recent investigations proposed applying an external electric field interrupt fibrils. This method non-invasive approach that certain benefit over others. We performed molecular dynamics (MD) simulations by on highly toxic fibrils gain molecular-level insight into disruption mechanisms. results revealed applied induces substantial changes conformation Furthermore, we show threshold value for strength required completely disrupt opening hydrophobic core fibril. Thus, our findings might serve as valuable foundation better understand mechanisms disaggregation process under field.

Language: Английский

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
A biological classification of Parkinson's disease: the SynNeurGe research diagnostic criteria DOI
Günter U. Höglinger, Charles H. Adler, Daniela Berg

et al.

The Lancet Neurology, Journal Year: 2024, Volume and Issue: 23(2), P. 191 - 204

Published: Jan. 22, 2024

Language: Английский

Citations

228
Proposal for a Biologic Staging System of Parkinson’s Disease DOI Creative Commons
Lana M. Chahine, Kalpana Merchant, Andrew Siderowf

et al.

Journal of Parkinson s Disease, Journal Year: 2023, Volume and Issue: 13(3), P. 297 - 309

Published: April 11, 2023

The Parkinson’s disease (PD) research field has seen the advent of several promising biomarkers and a deeper understanding clinical features from earliest stages pathology to manifest disease. Despite progress, biologically based PD staging system does not exist. Such would be useful framework within which model disease, develop validate biomarkers, guide therapeutic development, inform trials design. We propose that presence aggregated neuronal α-synuclein, dopaminergic neuron dysfunction/degeneration, signs symptoms identifies group individuals have Lewy body pathology, in early manifests with what is now referred as prodromal non-motor later manifestations related diseases defined by diagnostic criteria. Based on state field, we herein definition biology. present biologic basis for such review key assumptions evidence support proposed approach. identify gaps knowledge delineate crucial priorities will ultimate integrated PD.

Language: Английский

Citations

57
European intersocietal recommendations for the biomarker-based diagnosis of neurocognitive disorders DOI
Giovanni B. Frisoni, Cristina Festari, Federico Massa

et al.

The Lancet Neurology, Journal Year: 2024, Volume and Issue: 23(3), P. 302 - 312

Published: Feb. 15, 2024

Language: Английский

Citations

52
Artificial intelligence–coupled plasmonic infrared sensor for detection of structural protein biomarkers in neurodegenerative diseases DOI Creative Commons
Deepthy Kavungal, Pedro Magalhães,

Senthil T. Kumar

et al.

Science Advances, Journal Year: 2023, Volume and Issue: 9(28)

Published: July 12, 2023

Diagnosis of neurodegenerative disorders (NDDs) including Parkinson's disease and Alzheimer's is challenging owing to the lack tools detect preclinical biomarkers. The misfolding proteins into oligomeric fibrillar aggregates plays an important role in development progression NDDs, thus underscoring need for structural biomarker-based diagnostics. We developed immunoassay-coupled nanoplasmonic infrared metasurface sensor that detects linked such as alpha-synuclein, with specificity differentiates distinct species using their unique absorption signatures. augmented artificial neural network enabling unprecedented quantitative prediction protein mixture. microfluidic integrated can retrieve time-resolved absorbance fingerprints presence a complex biomatrix capable multiplexing simultaneous monitoring multiple pathology-associated Thus, our promising candidate clinical diagnosis monitoring, evaluation novel therapies.

Language: Английский

Citations

47
A Statement of the MDS on Biological Definition, Staging, and Classification of Parkinson's Disease DOI
Francisco Cardoso, Christopher G. Goetz, Tiago Mestre

et al.

Movement Disorders, Journal Year: 2023, Volume and Issue: 39(2), P. 259 - 266

Published: Dec. 13, 2023

Language: Английский

Citations

44
Bioactive Compounds of the Mediterranean Diet as Nutritional Support to Fight Neurodegenerative Disease DOI Open Access
Gianluca Antonio Franco,

Livia Interdonato,

Marika Cordaro

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(8), P. 7318 - 7318

Published: April 15, 2023

Neurodegenerative disorders are a widespread cause of morbidity and mortality worldwide, characterized by neuroinflammation, oxidative stress, neuronal depletion. They include selective malfunction progressive loss neurons, glial cells, neural networks in the brain spinal cord. There is an urgent need to develop new more effective therapeutic strategies combat these devastating diseases because, today, there no treatment that can cure degenerative diseases; however, we have many symptomatic treatments. Current nutritional approaches beginning reflect fundamental change our understanding health. The Mediterranean diet may protective effect on neurodegenerative process because it rich antioxidants, fiber, omega-3 polyunsaturated fatty acids. Increasing knowledge regarding impact regulation at genetic molecular levels changing way consider role nutrition, resulting dietary strategies. Natural products, thanks their bioactive compounds, recently undergone extensive exploration study for potential variety diseases. Targeting simultaneous multiple mechanisms action neuroprotection approach with could prevent cell death restore function damaged neurons. For reasons, this review will be focused natural products associations between Mediterranean-style (MD), diseases, markers neurodegeneration.

Language: Английский

Citations

36
Antibody-Mediated Clearance of Brain Amyloid-β: Mechanisms of Action, Effects of Natural and Monoclonal Anti-Aβ Antibodies, and Downstream Effects DOI Creative Commons
David A. Loeffler

Journal of Alzheimer s Disease Reports, Journal Year: 2023, Volume and Issue: 7(1), P. 873 - 899

Published: Aug. 7, 2023

Immunotherapeutic efforts to slow the clinical progression of Alzheimer’s disease (AD) by lowering brain amyloid-β (Aβ) have included Aβ vaccination, intravenous immunoglobulin (IVIG) products, and anti-Aβ monoclonal antibodies. Neither vaccination nor IVIG slowed progression. Despite conflicting phase III results, antibody Aducanumab received Food Drug Administration (FDA) approval for treatment AD in June 2021. The only treatments unequivocally demonstrated date are antibodies Lecanemab Donanemab. FDA January 2023 based on II results showing PET-detectable Aβ; released at that time indicated slowing Topline May Donanemab’s trial revealed primary secondary end points had been met. Antibody binding facilitates its clearance from via multiple mechanisms including promoting microglial phagocytosis, activating complement, dissolving fibrillar Aβ, antibody-Aβ complexes blood-brain barrier receptors. peripheral blood may also promote cerebral efflux a sink mechanism. According amyloid hypothesis, targeting progression, it must decrease downstream neuropathological processes tau aggregation phosphorylation (possibly) inflammation oxidative stress. This review discusses antibody-mediated clearance, findings trials involving IVIG, antibodies, effects reported those trials, approaches which might improve Aβ-clearing ability

Language: Английский

Citations

34
The Interplay between α-Synuclein and Microglia in α-Synucleinopathies DOI Open Access
Jacob Deyell, Manjari Sriparna, Mingyao Ying

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 2477 - 2477

Published: Jan. 27, 2023

Synucleinopathies are a set of devastating neurodegenerative diseases that share pathologic accumulation the protein α-synuclein (α-syn). This causes neuronal death resulting in irreversible dementia, deteriorating motor symptoms, and cognitive decline. While etiology these conditions remains largely unknown, microglia, resident immune cells central nervous system (CNS), have been consistently implicated pathogenesis synucleinopathies. Microglia generally believed to be neuroprotective early stages α-syn contribute further neurodegeneration chronic disease states. molecular mechanisms by which microglia achieve this role still being investigated, here we highlight major findings date. In review, describe how structural varieties inherently disordered result varied microglial receptor-mediated interactions. We also summarize receptors enable cellular recognition uptake α-syn. Lastly, review downstream effects processing within including spread other brain regions neuroinflammation Understanding mechanism interactions with is vital conceptualizing targets for novel therapeutic interventions. addition, given significant diversity pathophysiology synucleinopathies, such gauging all potential pathways state.

Language: Английский

Citations

33
Combining skin and olfactory α-synuclein seed amplification assays (SAA)—towards biomarker-driven phenotyping in synucleinopathies DOI Creative Commons
Anastasia Kuzkina,

Jonas Rößle,

A. Seger

et al.

npj Parkinson s Disease, Journal Year: 2023, Volume and Issue: 9(1)

Published: May 29, 2023

Seed amplification assays (SAA) are becoming commonly used in synucleinopathies to detect α-synuclein aggregates. Studies Parkinson's disease (PD) and isolated REM-sleep behavior disorder (iRBD) have shown a considerably lower sensitivity the olfactory epithelium than CSF or skin. To get an insight into (α-syn) distribution within nervous system reasons for low sensitivity, we compared SAA assessment of nasal brushings skin biopsies PD (n = 27) iRBD patients 18) unaffected controls 30). α-syn misfolding was overall found less skin, which could be partially explained by brushing matrix exerting inhibitory effect on aggregation. Importantly, not uniform: there higher deposition misfolded across all sampled tissues cohort (supporting notion RBD as marker more malignant subtype synucleinopathy) subgroup patients, detectable only epithelium, suggestive recently proposed brain-first subtype. Assaying diverse origins, such (part central system) (peripheral system), increase diagnostic accuracy allow better stratification patients.

Language: Английский

Citations

33