A5079356231- Amyotrophic Lateral Sclerosis Research
- Neurogenetic and Muscular Disorders Research
- Prion Diseases and Protein Misfolding
- 3D Printing in Biomedical Research
- Pluripotent Stem Cells Research
- Cellular Mechanics and Interactions
- Neurogenesis and neuroplasticity mechanisms
- Spectroscopy Techniques in Biomedical and Chemical Research
- RNA Research and Splicing
- Cell Image Analysis Techniques
- Radiopharmaceutical Chemistry and Applications
- Genetic Neurodegenerative Diseases
- thermodynamics and calorimetric analyses
- Tissue Engineering and Regenerative Medicine
- Neuroinflammation and Neurodegeneration Mechanisms
- Neuroscience and Neural Engineering
- Genomics, phytochemicals, and oxidative stress
- Additive Manufacturing and 3D Printing Technologies
- Spectroscopy and Chemometric Analyses
- Advanced Chemical Sensor Technologies
- Carcinogens and Genotoxicity Assessment
- Music Technology and Sound Studies
- RNA modifications and cancer
- Nerve injury and regeneration
- Autophagy in Disease and Therapy
King's College London
2017-2024
UK Dementia Research Institute
2023-2024
The Francis Crick Institute
2020-2024
University College London
2023
Imperial College London
2014-2022
NIHR Imperial Biomedical Research Centre
2014-2022
King's College - North Carolina
2020
University of Edinburgh
2011-2015
MRC Centre for Regenerative Medicine
2013-2015
Mott MacDonald (United Kingdom)
2011-2014
Glial proliferation and activation are associated with disease progression in amyotrophic lateral sclerosis (ALS) frontotemporal lobar dementia. In this study, we describe a unique platform to address the question of cell autonomy tran s active response DNA-binding protein (TDP-43) proteinopathies. We generated functional astroglia from human induced pluripotent stem cells carrying an ALS-causing TDP-43 mutation show that mutant astrocytes exhibit increased levels TDP-43, subcellular...
Transactive response DNA-binding (TDP-43) protein is the dominant disease in amyotrophic lateral sclerosis (ALS) and a subgroup of frontotemporal lobar degeneration (FTLD-TDP). Identification mutations gene encoding TDP-43 ( TARDBP ) familial ALS confirms mechanistic link between misaccumulation neurodegeneration provides an opportunity to study proteinopathies human neurons generated from patient fibroblasts by using induced pluripotent stem cells (iPSCs). Here, we report generation iPSCs...
Abstract Tissue engineering has offered unique opportunities for disease modeling and regenerative medicine; however, the success of these strategies is dependent on faithful reproduction native cellular organization. Here, it reported that ultrasound standing waves can be used to organize myoblast populations in material systems aligned muscle tissue constructs. Patterned engineered using type I collagen hydrogels exhibits significant anisotropy tensile strength, under mechanical...
Methylation of cytosine is a DNA modification associated with gene repression. Recently, novel modification, 5-hydroxymethylcytosine (5-hmC) has been discovered. Here we examine 5-hmC distribution during mammalian development and in cellular systems, show that the developmental dynamics are different from those 5-methylcytosine (5-mC); particular enriched embryonic contexts compared to adult tissues. A detectable signal appears pre-implantation starting at zygote stage, where paternal genome...
Abstract Forebrain neurons have weak intrinsic antioxidant defences compared with astrocytes, but the molecular basis and purpose of this is poorly understood. We show that early in mouse cortical neuronal development vitro vivo , expression master-regulator genes, transcription factor NF-E2-related-factor-2 (Nrf2), repressed by epigenetic inactivation its promoter. Consequently, contrast to astrocytes or young neurons, maturing possess negligible Nrf2-dependent defences, exhibit no...
Motor neurons (MNs) and astrocytes (ACs) are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), but their interaction sequence molecular events leading to MN death remain unresolved. Here, we optimized directed differentiation induced pluripotent stem cells (iPSCs) into highly enriched (> 85%) functional populations spinal cord MNs ACs. We identify significantly increased cytoplasmic TDP-43 ER stress as primary pathogenic patient-specific valosin-containing protein...
Cortical hyperexcitability and mislocalization of the RNA-binding protein TDP43 are highly conserved features in amyotrophic lateral sclerosis (ALS). Nevertheless, relationship between these phenomena remains poorly defined. Here, we showed that recapitulates pathology by upregulating shortened (sTDP43) splice isoforms. These truncated isoforms accumulated cytoplasm formed insoluble inclusions sequestered full-length via preserved N-terminal interactions. Consistent with findings, sTDP43...
Defects in organellar acidification indicate compromised or infected compartments. Recruitment of the autophagy-related ATG16L1 complex to pathologically neutralized organelles targets ubiquitin-like ATG8 molecules perturbed membranes. How this process is coupled proton gradient disruption unclear. Here, we reveal that V
The glial environment is an important determinant of neuronal health in experimental models neurodegeneration. Specifically, astrocytes have been shown, dependent on context, to be both injurious and protective. Human pluripotent stem cells offer a powerful new system improve our understanding the mechanisms underlying astrocyte-mediated neuroprotection. Here, we describe human embryonic cell (HESC)-based assess scope mechanism We first report generation enriched functional HESC-derived...
Significance Laminin-111 is one of the first extracellular matrix proteins expressed during embryogenesis and has been studied for decades, mainly because its major role in assembling basement membrane, but also it now become most popular cell culture substrates embryonic stem cells. However, considering importance this protein, laminin-111 plays remodeling—which not only great interest when seeking to understand cell–matrix interactions, using laminin as a substrate tissue engineering—is...
Neural tissue engineering (TE) represents a promising new avenue of therapy to support nerve recovery and regeneration. To recreate the complex environment in which neurons develop mature, ideal biomaterials for neural TE require number properties capabilities including appropriate biochemical physical cues adsorb release specific growth factors. Here, we present constructs based on electrospun serum albumin (SA) fibrous scaffolds. We doped our SA scaffolds with an iron-containing porphyrin,...
Analyzing lipid composition and distribution within the brain is important to study white matter pathologies that present focal demyelination lesions, such as multiple sclerosis. Some lesions can endogenously re-form myelin sheaths. Therapies aim enhance this repair process in order reduce neurodegeneration disability progression patients. In context, a lipidomic analysis providing both precise molecular classification well-defined localization crucial detect changes content. Here we develop...
Abstract The unique electrochemical properties of the conductive polymer poly(3,4‐ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) make it an attractive material for use in neural tissue engineering applications. However, inadequate mechanical properties, and difficulties processing lack biodegradability have hindered progress this field. Here, functionality PEDOT:PSS is improved by incorporating 3,4‐ethylenedioxythiophene (EDOT) oligomers, synthesized using a novel end‐capping...
A number of studies have recently shown how surface topography can alter the behavior and differentiation patterns different types stem cells. Although exact mechanisms molecular pathways involved remain unclear, a consistent portion literature points to epigenetic changes induced by nuclear remodeling. In this study, we investigate clinically relevant neural populations derived from human pluripotent cells when cultured on polydimethylsiloxane microgrooves (3 10 μm depth grooves) what are...
Neuronal circuits are complex networks formed by specific neuron connections across brain regions. Understanding their development is key to studying circuit-related dysfunctions in diseases. Human-induced pluripotent stem cell (iPSC) models aid this research but lack precise architecture, limiting insights into neuronal interactions and activity-dependent processes. Microfluidic technologies offer structural control restricted closed systems that hinder 3D integration, scalability,...
Multiple Sclerosis has two clinical phases reflecting distinct but inter-related pathological processes: focal inflammation drives the relapse-remitting stage and neurodegeneration represents principal substrate of secondary progression. In contrast to increasing number effective anti-inflammatory disease modifying treatments for disease, absence therapies progressive a major unmet need. This raises unanswered question whether elimination relapses will prevent subsequent progression if so...
Abstract Stem cell‐based experimental platforms for neuroscience can effectively model key mechanistic aspects of human development and disease. However, conventional culture systems often overlook the engineering constraints that cells face in vivo. This is particularly relevant neurons covering long range connections such as spinal motor (MNs). Their axons extend up to 1m length require a complex interplay mechanisms maintain cellular homeostasis. shorter cultures may not faithfully...
SUMMARY Axonal degeneration underlies neuromuscular disorders and neuropathies. Dysregulation of neurotrophic factors, such as brain-derived factor (BDNF), in the peripheral nervous system has long been established to exacerbate axonopathy. However, molecular programs controlled by BDNF that facilitate axonal regeneration transport are not well-understood. Here, we unravel transcriptomic phosphorylation landscape shaped human iPSC-derived motor neurons. Using SLAM-Seq, reveal stimulation...