A5006100200- Amyotrophic Lateral Sclerosis Research
- Neurogenetic and Muscular Disorders Research
- Mitochondrial Function and Pathology
- Parkinson's Disease Mechanisms and Treatments
- Cancer, Hypoxia, and Metabolism
- Heat shock proteins research
- Child Nutrition and Feeding Issues
- ATP Synthase and ATPases Research
- Alzheimer's disease research and treatments
- Protein Structure and Dynamics
- Eicosanoids and Hypertension Pharmacology
- Enzyme Structure and Function
- Cancer-related molecular mechanisms research
- Adenosine and Purinergic Signaling
- Biochemical Acid Research Studies
- biodegradable polymer synthesis and properties
- Medicinal Plant Pharmacodynamics Research
- Cholinesterase and Neurodegenerative Diseases
- Neuroinflammation and Neurodegeneration Mechanisms
- Neurological diseases and metabolism
- Immune Cell Function and Interaction
- S100 Proteins and Annexins
- Cerebral Palsy and Movement Disorders
- Metabolomics and Mass Spectrometry Studies
- Peroxisome Proliferator-Activated Receptors
University of Sheffield
2013-2024
First People’s Hospital of Zunyi
2021
Zunyi Medical University
2021
Xiangyang Central Hospital
2021
Allen Institute
2020
German Centre for Cardiovascular Research
2017
The Wallace H. Coulter Department of Biomedical Engineering
2017
Georgia Institute of Technology
2017
Ludwig-Maximilians-Universität München
2017
University of Manchester
2002-2005
Objective— Atherosclerosis develops near branches and bends of arteries that are exposed to low shear stress (mechanical drag). These sites characterized by excessive endothelial cell (EC) proliferation inflammation promote lesion initiation. The transcription factor HIF1α (hypoxia-inducible 1α) is canonically activated hypoxia has a role in plaque neovascularization. We studied the influence on activation contribution this noncanonical pathway Approach Results— Quantitative polymerase chain...
As clinical evidence supports a negative impact of dysfunctional energy metabolism on the disease progression in amyotrophic lateral sclerosis, it is vital to understand how metabolic pathways are altered and whether they can be restored slow progression. Possible approaches include increasing or rerouting catabolism alternative fuel sources supplement glycolytic mitochondrial such as glycogen, ketone bodies nucleosides. To analyse basis catabolic defect sclerosis we used novel phenotypic...
It is important to understand how the disease process affects metabolic pathways in amyotrophic lateral sclerosis and whether these can be manipulated ameliorate progression. To analyse basis of defect we used a phenotypic profiling approach. Using fibroblasts reprogrammed induced astrocytes from C9orf72 sporadic cases measured production rate reduced nicotinamide adenine dinucleotides (NADH) 91 potential energy substrates simultaneously. Our screening approach identified that have distinct...
Aims Amyotrophic lateral sclerosis ( ALS ) and primary PLS are two syndromic variants within the motor neurone disease spectrum. As most cases sporadic SALS ), this limits availability of cellular models for investigating pathogenic mechanisms therapeutic targets. The aim study was to use gene expression profiling evaluate fibroblasts as , establish whether dysregulated biological processes recapitulate those seen in central nervous system elucidate pathways that distinguish clinically...
The TIM10 chaperone facilitates the insertion of hydrophobic proteins at mitochondrial inner membrane. Here we report novel molecular mechanism assembly. This process crucially depends on oxidative folding in mitochondria and involves: (i) import subunits a Cys-reduced unfolded state; (ii) to an assembly-competent structure maintained by intramolecular disulfide bonding their four conserved cysteines; (iii) assembly oxidized zinc-devoid functional complex. We show that occurs vivo, whereas...
Compelling evidence indicates that oxidative stress contributes to motor neuron injury in amyotrophic lateral sclerosis (ALS), but antioxidant therapies have not yet achieved therapeutic benefit the clinic. The nuclear erythroid 2-related-factor 2 (Nrf2) transcription factor is a key regulator of an important neuroprotective response by driving expression multiple cytoprotective genes via its interaction with element (ARE). Dysregulation Nrf2-ARE system has been identified ALS models and...
The TIM10 complex, composed of the homologous proteins Tim10 and Tim9, chaperones hydrophobic inserted at mitochondrial inner membrane. A salient feature complex subunits is their conserved "twin CX3C" motif. Systematic mutational analysis all cysteines showed that underlying molecular defect impaired folding (demonstrated by circular dichroism, aberrant homo-oligomer formation, thiol trapping assays). As a result defective folding, clear functional consequences were manifested in (i)...
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of motor neurons. Substantial evidence implicates oxidative stress and mitochondrial dysfunction as early events in disease progression. Our aim was to ascertain whether mutation SOD1 protein increases metabolic functional susceptibility stress. Here we used neuron-like cell line (NSC34) stably transfected with various human mutant transgenes (G93A, G37R, H48Q) investigate...
The TIM10 complex is localized in the mitochondrial intermembrane space and mediates insertion of hydrophobic proteins at inner membrane. We have characterized assembly analyzed structural properties its subunits, Tim9 Tim10. Both are α-helical with a protease-resistant central domain, each self-associates to form mainly dimers trimers solution. Tim10 bound one another submicromolar affinity equimolar amounts assembled stable, significantly extended that was indistinguishable from native...
Mitochondrial dysfunction is a common feature of C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD); however, it remains unclear whether this cause or consequence the pathogenic process. Analysing multiple aspects mitochondrial biology across several Drosophila models -ALS/FTD, we found morphology, oxidative stress, and mitophagy are commonly affected, which correlated with progressive loss locomotor performance. Notably, only genetic manipulations that reversed stress...
Tim9 and Tim10 are essential components of the "small Tim" family proteins that facilitate insertion polytopic at inner mitochondrial membrane. The small Tims themselves imported from cytosol organized in specific translocation assemblies intermembrane space. Their conformational properties how these influence mechanism assembly remain poorly understood. Moreover, three-dimensional structure TIM10 complex is unknown. We have characterized structural their free assembled states using NMR,...
Hypoxia is a feature of neurodegenerative diseases, and can both directly indirectly impact on neuronal function through modulation glial function. Astrocytes play key role in regulating homeostasis within the central nervous system, mediate hypoxia-induced changes response to reduced oxygen availability. The current study performed detailed characterization transcriptomic profile astrocytes vitro. Human were cultured under normoxic (5% CO2, 95% air) or hypoxic conditions (1% O2, 5% 94% N2)...
Atherosclerotic plaques form unevenly due to disturbed blood flow, causing localized endothelial cell (EC) dysfunction. Obesity exacerbates this process, but the underlying molecular mechanisms are unclear. The transcription factor EPAS1 (HIF2A) has regulatory roles in endothelium, its involvement atherosclerosis remains unexplored. This study investigates potential interplay between EPAS1, obesity, and atherosclerosis.
Introduction: ALS is a neurodegenerative disorder characterised by progressive upper and lower motor neuron loss. A GGGGCC hexanucleotide repeat expansion (HRE) in the C9orf72 gene most common mutation found populations of European descent. Mitochondrial dysfunction has been observed C9orf72-ALS patients models disease, however reports on mitochondrial clearance via mitophagy are limited. Results: iNeurons from displayed reduced membrane potential mitophagy, due to reductions autophagosome...
Aging is a major risk factor for neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). As metabolic alterations are hallmark of aging and have previously been observed in ALS, it important to examine the effect context ALS function. Here, using newly established phenotypic approach, we examined on profile fibroblasts derived from cases compared controls. We found that an altered profile, which influenced by age. In control cases, significant increases with age NADH...
Abstract Amyotrophic lateral sclerosis is a rapidly progressive neurodegenerative disease that affects 1/350 individuals in the United Kingdom. The cause of amyotrophic unknown majority cases. Two-sample Mendelian randomization enables causal inference between an exposure, such as serum concentration specific metabolite, and risk. We obtained genome-wide association study summary statistics for concentrations 566 metabolites which were population matched with sclerosis. For each we performed...
Abstract We describe an autosomal dominant, multi‐generational, amyotrophic lateral sclerosis (ALS) pedigree in which disease co‐segregates with a heterozygous p.Y374X nonsense mutation within TDP‐43. Mislocalization of TDP‐43 and formation insoluble TDP‐43‐positive neuronal cytoplasmic inclusions is the hallmark pathology >95% ALS patients. Neuropathological examination single case for CNS tissue was available indicated typical lower motor neurons, but classical were absent from cortex....
Background and aimsPeople living with motor neuron disease (MND) frequently struggle to consume an optimal caloric intake. Often compounded by hypermetabolism, this can lead dysregulated energy homeostasis, prompting the onset of malnutrition associated weight loss. This is a poorer prognosis reduced survival. It therefore important establish appropriate nutritional goals ensure adequate best done measuring resting expenditure (mREE) using indirect calorimetry. However, calorimetry not...