A5075768239- Parkinson's Disease Mechanisms and Treatments
- Neurological disorders and treatments
- Nerve injury and regeneration
- Neuroscience and Neuropharmacology Research
- Autism Spectrum Disorder Research
- Neuroinflammation and Neurodegeneration Mechanisms
- Nuclear Receptors and Signaling
- Neurotransmitter Receptor Influence on Behavior
- RNA regulation and disease
- Neuroscience and Neural Engineering
- Genetic Neurodegenerative Diseases
- Botulinum Toxin and Related Neurological Disorders
- Cannabis and Cannabinoid Research
- Cellular transport and secretion
- RNA Interference and Gene Delivery
- Forensic Toxicology and Drug Analysis
- Autophagy in Disease and Therapy
- Adipose Tissue and Metabolism
- Psychedelics and Drug Studies
- Restless Legs Syndrome Research
- Sirtuins and Resveratrol in Medicine
- Neuropeptides and Animal Physiology
- Cancer Treatment and Pharmacology
- Sleep and Wakefulness Research
- Retinal Development and Disorders
Atuka (Canada)
2013-2025
University Health Network
2015-2024
Toronto Western Hospital
2015-2024
Krembil Research Institute
2016-2024
Huashan Hospital
2020-2024
Fudan University
2020-2024
Krembil Foundation
2024
Universitätsklinikum Gießen und Marburg
2017
Centre Hospitalier de l’Université de Montréal
2014
Hôpital Notre-Dame
2014
Little is known about key pathological events preceding overt neuronal degeneration in Parkinson's disease (PD) and alpha-synucleinopathy. Recombinant adeno-associated virus 2-mediated delivery of mutant (A53T) human alpha-synuclein into the substantia nigra (SN) under a neuron-specific synapsin promoter resulted protracted neurodegeneration with significant dopaminergic (DA) neuron loss by 17 weeks. As early as 4 weeks, there was an increase dopamine metabolite, DOPAC histologically, DA...
Abstract Background The etiology of Parkinson's disease (PD) remains elusive despite identification several genetic mutations. It is more likely that multiple factors converge to give rise PD than any single cause. Here we report inflammation can trigger degeneration dopamine (DA) neurons in an animal model disease. Methods We examined the effects on progressive 6-OHDA rat using immunohistochemistry, multiplex ELISA, and cell counting stereology. Results show a non-toxic dose...
α-Synuclein is a protein implicated in the etiopathogenesis of Parkinson's disease (PD). AAV1/2-driven overexpression human mutated A53T-α-synuclein rat and monkey substantia nigra (SN) induces degeneration nigral dopaminergic neurons decreases striatal dopamine tyrosine hydroxylase (TH). Given certain advantages mouse, especially it being amendable to genetic manipulation, translating AAV1/2-A53T α-synuclein model mice would be significant value. or AAV1/2 empty vector (EV) at concentration...
The pathological hallmarks of Parkinson's disease (PD) include the presence alpha-synuclein (α-syn) rich Lewy bodies and neurites loss dopaminergic (DA) neurons substantia nigra (SN). Animal models PD based on viral vector-mediated over-expression α-syn have been developed show evidence DA toxicity to varying degrees depending type virus used, its concentration, serotype vector employed. To date these variable, difficult reproduce, slow in their evolution achieve a desired phenotype,...
Abstract Parkinson’s disease is a progressive neurodegenerative disorder characterised by the accumulation of misfolded α-synuclein in selected brain regions, including substantia nigra pars compacta (SNpc), where marked loss dopaminergic neurons also observed. Yet, relationship between and neurotoxicity currently remains unclear. As principal route for degradation proteins mammalian cells, ubiquitin-proteasome system (UPS) critical maintenance cellular proteostasis. Misfolded impairs UPS...
Antigen-specific neuroinflammation and neurodegeneration are characteristic for neuroimmunological diseases. In Parkinson's disease (PD) pathogenesis, α-synuclein is a known culprit. Evidence α-synuclein-specific T cell responses was recently obtained in PD. Still, causative link between these dopaminergic had been lacking. We thus addressed the functional relevance of immune PD mouse model. utilized model which an Adeno-associated Vector 1/2 serotype (AAV1/2) expressing human mutated...
In Parkinson's disease (PD), loss of striatal dopaminergic (DA) terminals and degeneration DA neurons in the substantia nigra (SN) are associated with glial reactions. Such inflammatory processes commonly considered an epiphenomenon neuronal degeneration. However, there is increasing recognition role neuroinflammation as initiation factor neuron To investigate this issue, we established a new model brain inflammation by injecting Toll-like receptor 3 (TLR-3) agonist...
The pathological hallmarks of Parkinson's disease (PD) are degeneration dopamine (DA) neurons the substantia nigra (SN) and presence alpha-synuclein (α-syn)-rich Lewy bodies in DA cells that remain. To model these aspects disease, we previously showed high titer (5.1×10exp12 gp/ml) AAV1/2 driven expression A53T α-syn SN rats caused nigrostriatal pathology including a loss neurons, but also with toxicity GFP control group. In current study, evaluate effects two lower titers by dilution vector...
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a highly effective symptomatic therapy for motor deficits in Parkinson's disease (PD). An additional, disease-modifying effect has been suspected from studies toxin-based PD animal models, but these models do not reflect molecular pathology and progressive nature that would be required to evaluate action. Defining could radically change way which DBS used PD.We applied STN-DBS an adeno-associated virus (AAV) 1/2-driven human...
l -3,4-Dihydroxyphenylalanine ( -DOPA) is the most effective treatment for Parkinson's disease, but long-term -DOPA administration marred by emergence of motor complications, namely, dyskinesia and a shortening antiparkinsonian benefit (wearing-OFF). 3,4-Methylenedioxymethamphetamine (MDMA) unique in that it exerts antidyskinetic effects may enhance actions -DOPA. MDMA composed two enantiomers with different pharmacological profiles; here, we describe novel enantiospecific synthesis expand...
Degeneration of noradrenergic locus coeruleus neurons occurs during the prodromal phase Parkinson's disease and contributes to a variety non-motor symptoms, e.g. depression, anxiety REM sleep behavior disorder. This study was designed establish first α-synucleinopathy mouse model, which should provide sufficient information about time-course neurodegeneration, replicate cardinal histopathological features human neuropathology finally lead robust histological markers, are assess pathological...
Abstract Idiopathic rapid eye movement sleep behaviour disorder (RBD) is now recognized as an early manifestation of α-synucleinopathies. Increasing experimental studies demonstrate that manipulative lesion or inactivation the neurons within sublaterodorsal tegmental nucleus (also known subcoeruleus in humans) can induce RBD-like behaviours animals. As current RBD animal models are not established on basis α-synucleinopathy, they do represent pathological substrate idiopathic and thus cannot...
Abstract While GM1 may interact with α-synuclein in vitro to inhibit aggregation, the ability of protect against toxicity vivo has not been investigated. We used targeted adeno-associated viral vector (AAV) overexpression human mutant (A53T) rat substantia nigra (SN) produce degeneration SN dopamine neurons, loss striatal levels, and behavioral impairment. Some animals received daily ganglioside administration for 6 weeks, beginning 24 hours after AAV-A53T or delayed start 5 weeks 3...
Abstract Neuroinflammation has been suggested as a pathogenetic mechanism contributing to Parkinson’s disease (PD). However, anti-inflammatory treatment strategies have not yet established therapeutic option for PD patients. We used human α-synuclein mouse model of progressive examine the and neuroprotective effects inflammasome inhibition on dopaminergic (DA) neurons in substantia nigra (SN). As NLRP3 (NOD-, LRR- pyrin domain-containing 3)-inflammasome is core interface both adaptive innate...
Abstract In Parkinson's disease (PD), dyskinesia develops following long‐term treatment with 3,4‐dihydroxyphenylalanine ( L ‐dopa). Given the prominent role of opioid system in basal ganglia function, nonselective receptor antagonists have been tested for antidyskinetic efficacy clinic (naltrexone and naloxone), although without success. current study, ADL5510, a novel, orally active antagonist mu selectivity, was examined ‐dopa‐treated 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)...
Recent failures in clinical trials for disease modification Parkinson's have highlighted the need a non-human primate model of synucleinopathy underpinning dopaminergic neuron degeneration. The present study was defined to begin development such cynomolgus macaque. We validated surgical and vector parameters define means provide robust over-expression alpha-synuclein which is associated with Lewy-like pathology degeneration nigrostriatal pathway. Thus, an AAV1/2 incorporating strong...
Expression or phosphorylation levels of leucine-rich repeat kinase 2 (LRRK2) and its Rab substrates have strong potential as disease pharmacodynamic biomarkers. The main objective this study is therefore to assess the LRRK2-Rab pathway for use biomarkers in human, non-human primate (NHP) rat urine. With urine collected from human subjects animals, we applied an ultracentrifugation based fractionation protocol isolate small urinary extracellular vesicles (uEVs). We used western blot with...
Alzheimer's disease (AD) is often accompanied by extrapyramidal signs attributed to nigrostriatal dysfunction. The association between amyloid deposition and degeneration essentially unknown. We showed previously that the striatum substantia nigra of transgenic mice harboring familial AD (FAD)-linked APPswe/PS1ΔE9 mutants exhibit morphological alterations amyloid-β (Aβ) (Perez et al., 2004). In present study, we further investigated interaction Aβ dopaminergic dysfunction, correlating...