Alpha-synuclein in Parkinson’s disease and other synucleinopathies: from overt neurodegeneration back to early synaptic dysfunction

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(3)

Published: March 1, 2023

Abstract Although the discovery of critical role α-synuclein (α-syn) in pathogenesis Parkinson’s disease (PD) is now twenty-five years old, it still represents a milestone PD research. Abnormal forms α-syn trigger selective and progressive neuronal death through mitochondrial impairment, lysosomal dysfunction, alteration calcium homeostasis not only but also other α-syn-related neurodegenerative disorders such as dementia with Lewy bodies, multiple system atrophy, pure autonomic failure, REM sleep behavior disorder. Furthermore, α-syn-dependent early synaptic plastic alterations underlying mechanisms preceding overt neurodegeneration have attracted great interest. In particular, presence inflammation experimental models patients, occurring before deposition spreading α-syn, suggests mechanistic link between dysfunction. The knowledge these seminal importance to support research on reliable biomarkers precociously identify possible disease-modifying therapies targeting α-syn. this review, we will discuss issues, providing state art protein synucleinopathies.

Language: Английский

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A biological definition of neuronal α-synuclein disease: towards an integrated staging system for research

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

Published: Jan. 22, 2024

Language: Английский

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A biological classification of Parkinson's disease: the SynNeurGe research diagnostic criteria

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

Published: Jan. 22, 2024

Language: Английский

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Propagative α-synuclein seeds as serum biomarkers for synucleinopathies

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(6), P. 1448 - 1455

Published: May 29, 2023

Abnormal α-synuclein aggregation is a key pathological feature of group neurodegenerative diseases known as synucleinopathies, which include Parkinson's disease (PD), dementia with Lewy bodies and multiple system atrophy (MSA). The pathogenic β-sheet seed conformation found in various tissues, suggesting potential biomarker, but few studies have been able to reliably detect these seeds serum samples. In this study, we developed modified assay system, called immunoprecipitation-based real-time quaking-induced conversion (IP/RT-QuIC), enables the detection individuals synucleinopathies. our internal first second cohorts, IP/RT-QuIC showed high diagnostic performance for differentiating PD versus controls (area under curve (AUC): 0.96 (95% confidence interval (CI) 0.95-0.99)/AUC: 0.93 CI 0.84-1.00)) MSA (AUC: 0.64 0.49-0.79)/AUC: 0.73 0.49-0.98)). also 0.86 0.74-0.99)) 0.80 0.65-0.97)) from blinded external cohort. Notably, amplified maintained disease-specific properties, allowing differentiation samples MSA. summary, here present novel platform that may allow synucleinopathies using

Language: Английский

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Cognitive effects of Lewy body pathology in clinically unimpaired individuals

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(8), P. 1971 - 1978

Published: July 18, 2023

Abstract α-Synuclein aggregates constitute the pathology of Lewy body (LB) disease. Little is known about effects LB in preclinical (presymptomatic) individuals, either as isolated or coexisting with Alzheimer’s disease (AD) (β-amyloid (Aβ) and tau). We examined using a cerebrospinal fluid α-synuclein-seed amplification assay 1,182 cognitively neurologically unimpaired participants from BioFINDER study: 8% were positive, 26% Aβ positive (13% those positive) 16% tau positive. positivity occurred more often presence but not positivity. had independently negative on cross-sectional longitudinal global cognition memory attention/executive function. Tau cognitive similar magnitude, these less pronounced for Aβ. Participants both AD (Aβ tau) exhibited faster decline than only pathology. LB, AD, was associated reduced sense smell. Only LB-positive progressed to clinical over 10 years. These results are important individualized prognosis, recruitment choice outcome measures trials, also design early trials because >10% individuals have

Language: Английский

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Clinical effects of Lewy body pathology in cognitively impaired individuals

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(8), P. 1964 - 1970

Published: July 18, 2023

There is poor knowledge about the clinical effects of Lewy body (LB) pathology in patients with cognitive impairment, especially when coexisting Alzheimer's disease (AD) (amyloid-β and tau). Using a seed amplification assay, we analyzed cerebrospinal fluid for misfolded LB-associated α-synuclein 883 memory clinic mild impairment or dementia from BioFINDER study. Twenty-three percent had LB pathology, which only 21% fulfilled criteria Parkinson's bodies at baseline. Among these LB-positive patients, 48% AD pathology. Fifty-four whole sample (17% 24% were also LB-positive). When examining independent cross-sectional effects, but not amyloid-β tau, was associated hallucinations worse attention/executive, visuospatial motor function. faster longitudinal decline all examined functions, amyloid-β, stage baseline diagnosis bodies/Parkinson's disease. status provides better precision-medicine approach to predict trajectories biomarkers diagnosis, could have implications management design drug trials.

Language: Английский

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Proposal for a Biologic Staging System of Parkinson’s Disease

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

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Biomarkers for parkinsonian disorders in CNS-originating EVs: promise and challenges

Acta Neuropathologica, Journal Year: 2023, Volume and Issue: 145(5), P. 515 - 540

Published: April 4, 2023

Abstract Extracellular vesicles (EVs), including exosomes, microvesicles, and oncosomes, are nano-sized particles enclosed by a lipid bilayer. EVs released virtually all eukaryotic cells have been shown to contribute intercellular communication transporting proteins, lipids, nucleic acids. In the context of neurodegenerative diseases, may carry toxic, misfolded forms amyloidogenic proteins facilitate their spread recipient in central nervous system (CNS). CNS-originating can cross blood–brain barrier into bloodstream be found other body fluids, saliva, tears, urine. originating CNS represent an attractive source biomarkers for because they contain cell- cell state-specific biological materials. recent years, multiple papers reported use this strategy identification quantitation Parkinson’s disease atypical parkinsonian disorders. However, certain technical issues yet standardized, such as best surface markers isolation type-specific validating cellular origin EVs. Here, we review research using biomarker studies, primarily disorders, highlight challenges, propose strategies overcoming them.

Language: Английский

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α‐Synuclein Seed Amplification Assays in the Diagnosis of Synucleinopathies Using Cerebrospinal Fluid—A Systematic Review and Meta‐Analysis

Movement Disorders Clinical Practice, Journal Year: 2023, Volume and Issue: 10(5), P. 737 - 747

Published: March 3, 2023

Real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA) have been developed to detect minute amounts of amyloidogenic proteins via techniques used misfolded α-synuclein (αSyn) aggregates in the cerebrospinal fluid (CSF) other source materials patients with Parkinson's Disease synucleinopathies.The aim this systematic review meta-analysis was evaluate diagnostic accuracy αSyn seed assays (αSyn-SAAs), including RT-QuIC PMCA, using CSF as material differentiate synucleinopathies from controls.The electronic MEDLINE database PubMed searched for relevant articles published until June 30, 2022. Study quality assessment performed QUADAS-2 toolbox. A random effects bivariate model exploited data synthesis.Our identified 27 eligible studies according predefined inclusion criteria, which 22 were included final analysis. Overall, 1855 1378 non-synucleinopathies control subjects meta-analysis. The pooled sensitivity specificity controls αSyn-SAA 0.88 (95% CI, 0.82-0.93) 0.95 0.92-0.97), respectively. Evaluating performance a subgroup analysis detection multiple system atrophy decreased 0.30 0.11-0.59).While our study clearly demonstrated high PMCA differentiating Lewy bodies controls, results diagnosis less robust.

Language: Английский

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Cell–cell communication: new insights and clinical implications

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 7, 2024

Multicellular organisms are composed of diverse cell types that must coordinate their behaviors through communication. Cell-cell communication (CCC) is essential for growth, development, differentiation, tissue and organ formation, maintenance, physiological regulation. Cells communicate direct contact or at a distance using ligand-receptor interactions. So cellular encompasses two processes: signal conduction generation intercellular transmission signals, transduction reception procession signals. Deciphering networks critical understanding metabolism. First, we comprehensively review the historical milestones in CCC studies, followed by detailed description mechanisms molecule importance main signaling pathways they mediate maintaining biological functions. Then systematically introduce series human diseases caused abnormalities progress clinical applications. Finally, summarize various methods monitoring interactions, including imaging, proximity-based chemical labeling, mechanical force analysis, downstream analysis strategies, single-cell technologies. These aim to illustrate how functions depend on these interactions complexity regulatory regulate crucial processes, homeostasis, immune responses diseases. In addition, this enhances our processes occur after cell-cell binding, highlighting its application discovering new therapeutic targets biomarkers related precision medicine. This collective provides foundation developing targeted drugs personalized treatments.

Language: Английский

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