Neuromelanin accumulation drives endogenous synucleinopathy in non-human primates DOI Creative Commons
Julia Chocarro, Alberto J. Rico, Goiaz Ariznabarreta

et al.

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

Published: Aug. 6, 2023

Abstract Although neuromelanin (NMel) is a dark pigment characteristic of dopaminergic neurons in the human substantia nigra pars compacta (SNpc), its potential role pathogenesis Parkinson’s disease (PD) has often been neglected since most commonly used laboratory animals lack NMel. Here we took advantage adeno-associated viral vectors encoding tyrosinase gene for triggering time-dependent NMel accumulation within SNpc macaques up to similar levels pigmentation as observed elderly humans. Furthermore, induced an endogenous synucleinopathy mimicking intracellular inclusions typically PD together with progressive degeneration NMel-expressing neurons. Moreover, Lewy body-like were cortical areas frontal lobe receiving innervation, supporting circuit-specific anterograde spread by permissive trans-synaptic templating. In summary, conducted strategy resulted development and characterization new macaque model matching known neuropathology this disorder unprecedented accuracy. Most importantly, evidence provided showing that aggregation alpha-synuclein triggered accumulation, therefore any therapeutic approach intended decrease may provide appealing choices successful implementation novel therapeutics.

Language: Английский

Exercise as medicine in Parkinson’s disease DOI
Martin Langeskov‐Christensen, Erika Franzén, Lars G. Hvid

et al.

Journal of Neurology Neurosurgery & Psychiatry, Journal Year: 2024, Volume and Issue: 95(11), P. 1077 - 1088

Published: Feb. 28, 2024

Parkinson’s disease (PD) is an incurable and progressive neurological disorder leading to deleterious motor non-motor consequences. Presently, no pharmacological agents can prevent PD evolution or progression, while symptomatic treatments have limited effects in certain domains cause side effects. Identification of interventions that prevent, slow, halt mitigate the therefore pivotal. Exercise safe represents a cornerstone rehabilitation, but exercise may even more fundamental benefits could change clinical practice. In PD, existing knowledge base supports as (1) protective lifestyle factor preventing (ie, primary prevention), (2) potential disease-modifying therapy secondary prevention) (3) effective treatment tertiary prevention). Based on current evidence, paradigm shift proposed, stating should be individually prescribed medicine persons with at early stage, alongside conventional medical treatment.

Language: Английский

Citations

22
Age and sex differentially shape brain networks in Parkinson's disease DOI Creative Commons
Zhichun Chen, Bin Wu, Guanglu Li

et al.

CNS Neuroscience & Therapeutics, Journal Year: 2023, Volume and Issue: 29(7), P. 1907 - 1922

Published: March 8, 2023

Abstract Aims Age and sex are important individual factors modifying the clinical symptoms of patients with Parkinson's disease (PD). Our goal is to evaluate effects age on brain networks manifestations PD patients. Methods participants ( n = 198) receiving functional magnetic resonance imaging from Progression Markers Initiative database were investigated. Participants classified into lower quartile group (age rank: 0%~25%), interquartile 26%~75%), upper 76%~100%) according their quartiles examine how shapes network topology. The differences topological properties between male female also Results in exhibited disrupted topology white matter impaired integrity fibers compared group. In contrast, preferentially shaped small‐world gray covariance network. Differential metrics mediated cognitive function Conclusion have diverse structural patients, highlighting roles management PD.

Language: Английский

Citations

24
The Absence of Gastrointestinal Redox Dyshomeostasis in the Brain-First Rat Model of Parkinson’s Disease Induced by Bilateral Intrastriatal 6-Hydroxydopamine DOI Creative Commons
Jan Homolak, Mihovil Joja, Gracia Grabarić

et al.

Molecular Neurobiology, Journal Year: 2024, Volume and Issue: 61(8), P. 5481 - 5493

Published: Jan. 10, 2024

The gut-brain axis plays an important role in Parkinson's disease (PD) by acting as a route for vagal propagation of aggregated α-synuclein the gut-first endophenotype and mediator gastrointestinal dyshomeostasis via nigro-vagal pathway brain-first disease. One mechanism which may promote PD is regulating redox homeostasis overwhelming evidence suggests that oxidative stress key etiopathogenesis progression tract maintains organism critical barrier to environmental microbiological electrophilic challenges. present aim was utilize bilateral intrastriatal 6-hydroxydopamine (6-OHDA) model study effects isolated central pathology on tract. Three-month-old male Wistar rats were either not treated (intact controls; CTR) or bilaterally intrastriatally with vehicle (CIS) 6-OHDA (6-OHDA). Motor deficits assessed rotarod performance test, duodenum, ileum, colon dissected biochemical analyses 12 weeks after treatment. Lipid peroxidation, total antioxidant capacity, low-molecular-weight thiols, protein sulfhydryls, activity Mn/Fe superoxide dismutases, azide-insensitive catalase/peroxidase measured. Both univariate multivariate models analyzing biomarkers indicate significant disturbances balance are present. findings demonstrate motor impairment observed can occur without concurrent imbalances system.

Language: Английский

Citations

5
Neuromelanin accumulation drives endogenous synucleinopathy in non-human primates DOI Creative Commons
Julia Chocarro, Alberto J. Rico, Goiaz Ariznabarreta

et al.

Brain, Journal Year: 2023, Volume and Issue: 146(12), P. 5000 - 5014

Published: Sept. 28, 2023

Although neuromelanin is a dark pigment characteristic of dopaminergic neurons in the human substantia nigra pars compacta, its potential role pathogenesis Parkinson's disease (PD) has often been neglected since most commonly used laboratory animals lack neuromelanin. Here we took advantage adeno-associated viral vectors encoding tyrosinase gene for triggering time-dependent accumulation within compacta macaques up to similar levels pigmentation as observed elderly humans. Furthermore, induced an endogenous synucleinopathy mimicking intracellular inclusions typically PD together with progressive degeneration neuromelanin-expressing neurons. Moreover, Lewy body-like were cortical areas frontal lobe receiving innervation, supporting circuit-specific anterograde spread by permissive trans-synaptic templating. In summary, conducted strategy resulted development and characterization new macaque model matching known neuropathology this disorder unprecedented accuracy. Most importantly, evidence provided showing that aggregation α-synuclein triggered accumulation, therefore any therapeutic approach intended decrease may provide appealing choices successful implementation novel therapeutics.

Language: Английский

Citations

12
Identification of Clec7a as the therapeutic target of rTMS in alleviating Parkinson's disease: targeting neuroinflammation DOI Creative Commons
Xueyun Chen,

Sining Feng,

Yin Bao

et al.

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Journal Year: 2023, Volume and Issue: 1869(8), P. 166814 - 166814

Published: July 25, 2023

Language: Английский

Citations

11
PADS-Net: GAN-based radiomics using multi-task network of denoising and segmentation for ultrasonic diagnosis of Parkinson disease DOI

Yiwen Shen,

Li Chen, Jieyi Liu

et al.

Computerized Medical Imaging and Graphics, Journal Year: 2025, Volume and Issue: 120, P. 102490 - 102490

Published: Jan. 8, 2025

Language: Английский

Citations

0
Selecting the Best Animal Model of Parkinson’s Disease for Your Research Purpose: Insight from in vivo PET Imaging Studies DOI
Caroline Cristiano Real, Karina Henrique Binda, Majken Borup Thomsen

et al.

Current Neuropharmacology, Journal Year: 2023, Volume and Issue: 21(5), P. 1241 - 1272

Published: Feb. 17, 2023

Parkinson's disease (PD) is a debilitating neurodegenerative multisystem disorder leading to motor and non-motor symptoms in millions of individuals. Despite intense research, there still no cure, early biomarkers are lacking. Animal models PD have been inspired by basic elements its pathogenesis, such as dopamine dysfunction, alpha-synuclein accumulation, neuroinflammation disruption protein degradation, these crucial for deeper understanding the mechanisms pathology, identification biomarkers, evaluation novel therapies. Imaging non-invasive tools assess progression response therapies; their discovery validation an active field translational research. Here, we highlight different considerations animal that can be applied future terms suitability answer research questions. We provide reader with important best choice model use based on features each model, including issues related species. In addition, positron emission tomography studies conducted last 5 years presented. With variety species, interventions genetic information, most appropriate questions daunting, especially since single recapitulates all aspects this complex disorder. Appropriate conjunction vivo molecular imaging tools, if selected properly, powerful combination assessment therapies developing diagnosis.

Language: Английский

Citations

8
α-Synuclein oligomers and fibrils: partners in crime in synucleinopathies DOI Creative Commons
Alessandra Bigi, Roberta Cascella, Cristina Cecchi

et al.

Neural Regeneration Research, Journal Year: 2023, Volume and Issue: 18(11), P. 2332 - 2342

Published: March 11, 2023

The misfolding and aggregation of α-synuclein is the general hallmark a group devastating neurodegenerative pathologies referred to as synucleinopathies, such Parkinson's disease, dementia with Lewy bodies, multiple system atrophy. In conditions, range different misfolded aggregates, including oligomers, protofibrils, fibrils, are present both in neurons glial cells. Growing experimental evidence supports proposition that soluble oligomeric assemblies, formed during early phases process, major culprits neuronal toxicity; at same time, fibrillar conformers appear be most efficient propagating among interconnected neurons, thus contributing spreading pathology. Moreover, fibrils have been recently reported release highly toxic species, responsible for an immediate dysfunction recipient neurons. this review, we discuss current knowledge about plethora mechanisms cellular caused by oligomers neurodegeneration synucleinopathies.

Language: Английский

Citations

8
Current insights and assumptions on α-synuclein in Lewy body disease DOI Creative Commons
Rehana K. Leak,

Rachel N. Clark,

Muslim Abbas

et al.

Acta Neuropathologica, Journal Year: 2024, Volume and Issue: 148(1)

Published: Aug. 14, 2024

Lewy body disorders are heterogeneous neurological conditions defined by intracellular inclusions composed of misshapen α-synuclein protein aggregates. Although aggregates only one component and not strictly coupled to neurodegeneration, evidence suggests they seed the propagation pathology within across cells. Genetic mutations, genomic multiplications, sequence polymorphisms gene encoding also causally linked disease. In nonfamilial cases disease, disease trigger remains unidentified but may range from industrial/agricultural toxicants natural sources poisons microbial pathogens. Perhaps due these peripheral exposures, appear at early stages in brain regions connected with cranial nerves I X, which interface inhaled ingested environmental elements nasal or gastrointestinal cavities. Irrespective its identity, a stealthy most likely shifts soluble (directly indirectly) into insoluble, cross-β-sheet Indeed, β-sheet-rich self-replicating multimers reside patient plasma, cerebrospinal fluid, other tissues, can be subjected amplification assays. Thus, clinicians should able capitalize on assays stratify patients potential responders versus non-responders future clinical trials targeted therapies. Here, we briefly review current understanding speculate pathophysiological processes underlying transmission α-synucleinopathy neuraxis.

Language: Английский

Citations

3
Longitudinal Changes in Mitochondrial DNA Copy Number and Telomere Length in Patients with Parkinson’s Disease DOI Open Access
Alberto Ortega‐Vázquez, Salvador Sánchez-Badajos, Miguel Ángel Ramírez-García

et al.

Genes, Journal Year: 2023, Volume and Issue: 14(10), P. 1913 - 1913

Published: Oct. 7, 2023

Parkinson's disease (PD) pathophysiology includes mitochondrial dysfunction, neuroinflammation, and aging as its biggest risk factors. Mitochondrial DNA copy number (mtDNA-CN) telomere length (TL) are biological markers with inconclusive results regarding their association PD. A case-control study was used to measure TL mtDNA-CN using qPCR in PBMCs. PD patients were naive at baseline (T0) followed-up one (T1) two (T2) years after the dopaminergic treatment (DRT). Plasmatic cytokines determined by ELISA all participants, along clinical parameters of T0. While shorter vs. controls time points evaluated (p < 0.01), showed no differences. An increase observed treated ones 0.001). Our statistical model analyzed both covariates, showing a strong correlation between them (r = 0.57, p IL-17A levels positively correlating only untreated 0.45, 0.05). could be useful for monitoring inflammation progression or response DRT might modulate mtDNA-CN, reflecting compensatory mechanism counteract dysfunction PD, but this needs further investigation.

Language: Английский

Citations

8