A5026621001- Parkinson's Disease Mechanisms and Treatments
- Neurological disorders and treatments
- Genetic Neurodegenerative Diseases
- Mitochondrial Function and Pathology
- Neurological diseases and metabolism
- Zebrafish Biomedical Research Applications
- Trace Elements in Health
- Nuclear Receptors and Signaling
- Lysosomal Storage Disorders Research
- Metabolism and Genetic Disorders
- Heavy Metal Exposure and Toxicity
- Autophagy in Disease and Therapy
- RNA regulation and disease
- Alzheimer's disease research and treatments
- Neurogenetic and Muscular Disorders Research
- Autism Spectrum Disorder Research
- Folate and B Vitamins Research
- Obsessive-Compulsive Spectrum Disorders
- Amyotrophic Lateral Sclerosis Research
- Hereditary Neurological Disorders
- Genetics and Neurodevelopmental Disorders
- Restless Legs Syndrome Research
- Health Systems, Economic Evaluations, Quality of Life
- Neuroinflammation and Neurodegeneration Mechanisms
- Neurological and metabolic disorders
University of Sheffield
2016-2025
Heidelberg University
2003-2020
Royal Hallamshire Hospital
2013-2020
Sheffield Teaching Hospitals NHS Foundation Trust
2013-2020
Vanderbilt University
2008-2020
University Hospital Heidelberg
2020
Leeds Teaching Hospitals NHS Trust
2020
Royal North Shore Hospital
2020
Northern Sydney Local Health District
2020
The University of Sydney
2020
Previous studies have failed to identify mutations in the Wilson's disease gene ATP7B a significant number of clinically diagnosed cases. This has led concerns about genetic heterogeneity for this condition but also suggested presence unusual mutational mechanisms. We now present our findings 181 patients from United Kingdom with and biochemically confirmed disease. A total 116 different were detected, 32 which are novel. The overall mutation detection frequency was 98%. likelihood genes...
There are marked mitochondrial abnormalities in parkin-knock-out Drosophila and other model systems. The aim of our study was to determine function morphology parkin-mutant patients. We also investigated whether pharmacological rescue impaired may be possible human tissue.
<h3>Objective:</h3> The <i>LRRK2</i><sup>G2019S</sup> mutation is the most common identifiable cause for Parkinson disease (PD), but underlying mechanisms leading to neuronal cell death remain largely unclear. Impaired mitochondrial function and morphology have been described in different vivo vitro model systems of early-onset PD (EOPD) as well EOPD patient tissue. aim our study was assess mutant tissue determine whether impaired are shared features late-onset PD. <h3>Methods:</h3> Skin...
Mutations in DJ-1 lead to early onset Parkinson's disease (PD). The aim of this study was elucidate further the underlying mechanisms leading neuronal cell death deficiency vivo and determine whether observed loss could be prevented pharmacologically. Inactivation zebrafish, Danio rerio, resulted dopaminergic neurons after exposure hydrogen peroxide proteasome inhibitor MG132. knockdown by itself already increased p53 Bax expression levels prior toxin without marked death, suggesting...
Currently, only symptomatic therapy is available for Parkinson's disease. The zebrafish a vertebrate animal model ideally suited high throughput compound screening to identify disease-modifying compounds We have developed Parkin deficiency, the most commonly mutated gene in early onset protein 62% identical its human counterpart with 78% identity functionally relevant regions. parkin expressed throughout development and ubiquitously adult tissue. Abrogation of activity leads significant...
Rapid eye movement (REM) sleep behavior disorder (RBD) is the most specific marker of prodromal alpha-synucleinopathies. We sought to delineate baseline clinical characteristics RBD and evaluate risk stratification models.Clinical assessments were performed in 171 RBD, 296 control, 119 untreated Parkinson's (PD) participants. Putative measures assessed as predictors neurodegeneration, Movement Disorders Society (MDS) criteria for PD applied. Participants screened common leucine-rich repeat...
The previous finding of an immunologic response primarily directed against transglutaminase (TG)6 in patients with gluten ataxia (GA) led us to investigate the role TG6 antibodies diagnosing GA.This was a prospective cohort study. We recruited from ataxia, gluten/neurology, celiac disease (CD), and movement disorder clinics based at Royal Hallamshire Hospital (Sheffield, UK) CD clinic, Tampere University (Tampere, Finland). groups included idiopathic sporadic GA, CD, neurology healthy...
To further characterize mitochondrial dysfunction in LRRK2(G2019S) mutant Parkinson disease (PD) patient tissue (M-LRRK2(G2019S)), determine whether ursodeoxycholic acid (UDCA) also exerts a beneficial effect on nonmanifesting mutation carriers (NM-LRRK2(G2019S)), and assess UDCA for its neuronal vivo.Intracellular adenosine 5'-triphosphate (ATP) levels, oxygen consumption, activity of the individual complexes respiratory chain as well morphology were measured M-LRRK2(G2019S),...
Previous drug screens aiming to identify disease-modifying compounds for Parkinson's disease have typically been based on toxin-induced in vitro and vivo models of this neurodegenerative condition. All these failed a reliable effect subsequent clinical trials. We now established novel approach, namely screen an entire compound library directly patient tissue with rescue mitochondrial dysfunction as crucial pathogenic mechanism disease. The chosen Microsource Compound contains 2000 compounds,...
Autosomal recessively inherited glucocerebrosidase 1 (GBA1) mutations cause the lysosomal storage disorder Gaucher's disease (GD). Heterozygous GBA1 (GBA1+/−) are most common risk factor for Parkinson's (PD). Previous studies typically focused on interaction between reduction of (enzymatic) activity in GBA1+/− carriers and alpha-synuclein-mediated neurotoxicity. However, it is unclear whether other mechanisms also contribute to increased PD carriers. The zebrafish genome does not contain...
Optimizing the shape of a nanovector influences its interaction with cell and determines internalization kinetics. Block copolymer amphiphiles self-assemble into monodisperse structures in aqueous solutions have been explored extensively as drug delivery vectors. However, structure self-assembled block copolymers has mainly limited to spherical vesicles or worm-like micelles. Here we show controlled formation purification tubular polymersomes, long cylindrical vesicles. Tubular polymersomes...
Abstract Background Rescue of mitochondrial function is a promising neuroprotective strategy for Parkinson's disease (PD). Ursodeoxycholic acid (UDCA) has shown considerable promise as rescue agent across range preclinical in vitro and vivo models PD. Objectives To investigate the safety tolerability high‐dose UDCA PD determine midbrain target engagement. Methods The UP (UDCA PD) study was phase II, randomized, double‐blind, placebo‐controlled trial (30 mg/kg daily, 2:1 randomization vs....
Abstract PGC-1α plays a central role in maintaining mitochondrial and energy metabolism homeostasis, linking external stimuli to transcriptional co-activation of genes involved adaptive age-related pathways. The carboxyl-terminus encodes serine/arginine-rich (RS) region an RNA recognition motif, however the RNA-processing function(s) were poorly investigated over past 20 years. Here, we show that RS domain human directly interacts with nuclear export receptor NXF1. Inducible depletion...