A5090604330- Genomics, phytochemicals, and oxidative stress
- Neuroinflammation and Neurodegeneration Mechanisms
- Neuroscience and Neuropharmacology Research
- Circadian rhythm and melatonin
- Amyotrophic Lateral Sclerosis Research
- Autophagy in Disease and Therapy
- Mitochondrial Function and Pathology
- Genetics and Neurodevelopmental Disorders
- Neurogenesis and neuroplasticity mechanisms
- Anesthesia and Neurotoxicity Research
- Ubiquitin and proteasome pathways
- Parkinson's Disease Mechanisms and Treatments
- Adipose Tissue and Metabolism
- ATP Synthase and ATPases Research
- Genetic Neurodegenerative Diseases
- Redox biology and oxidative stress
- Nuclear Receptors and Signaling
- Stress Responses and Cortisol
- Ion channel regulation and function
- Medicinal Plants and Bioactive Compounds
- Intensive Care Unit Cognitive Disorders
- Neurological Disease Mechanisms and Treatments
University of Edinburgh
2014-2023
UK Dementia Research Institute
2021-2023
University of Sheffield
2020-2023
Mission Therapeutics (United Kingdom)
2023
Abstract The influence that neurons exert on astrocytic function is poorly understood. To investigate this, we first developed a system combining cortical and astrocytes from closely related species, followed by RNA-seq in silico species separation. This approach uncovers wide programme of neuron-induced gene expression, involving Notch signalling, which drives maintains maturity neurotransmitter uptake function, conserved human development, disrupted neurodegeneration. Separately, hundreds...
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...
Abstract Mutations in SNCA, the gene encoding α-synuclein (αSyn), cause familial Parkinson’s disease (PD) and aberrant αSyn is a key pathological hallmark of idiopathic PD. This α-synucleinopathy leads to mitochondrial dysfunction, which may drive dopaminergic neurodegeneration. PARKIN PINK1, mutated autosomal recessive PD, regulate preferential autophagic clearance dysfunctional mitochondria (“mitophagy”) by inducing ubiquitylation proteins, process counteracted deubiquitylation via USP30....
Abstract Astrocytes are highly specialised cells, responsible for CNS homeostasis and neuronal activity. Lack of human in vitro systems able to recapitulate the functional changes affecting astrocytes during ageing represents a major limitation studying mechanisms potential therapies aiming preserve health. Here, we show that induced from fibroblasts donors their childhood or adulthood display age‐related transcriptional differences functionally diverge spectrum age‐associated features, such...
Hexanucleotide repeat expansions in C9ORF72 are the most common genetic cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Studies have shown that hexanucleotide noncanonical translation transcripts into neurotoxic dipeptide proteins (DPRs) contribute to neurodegeneration. We show a cell-penetrant peptide blocked nuclear export -repeat HEK293T cells by competing with interaction between SR-rich splicing factor 1 (SRSF1) (NXF1). The also toxic DPRs...
Amyotrophic lateral sclerosis (ALS) is characterised by motor neuron (MN) death; however, astrocytes play a key role in disease pathogenesis. Developments the field of artificial intelligence (AI) have potential to impact drug discovery multiple ways, including rapid identification repurposing candidates. A combination natural language processing and deep learning algorithms was used generate knowledge graph based on scientific literature, omics chemical databases, other public sources with...
Uptake of Ca2+ into the mitochondrial matrix controls cellular metabolism and survival-death pathways. Several genes are implicated in controlling uptake (mitochondrial calcium regulatory genes, MCRGs), however, less is known about factors which influence their expression level. Here we have compared MCRG mRNA expression, neural cells differing type (cortical neurons vs. astrocytes), neuronal subtype (CA3 CA1 hippocampus) response to influx, using a combination qPCR RNA-seq analysis. Of...
Abstract Many neurodegenerative diseases are associated with neuronal misfolded protein accumulation, indicating a need for proteostasis-promoting strategies. Here we show that de-repressing the transcription factor Nrf2, epigenetically shut-off in early development, can prevent aggregate accumulation. Using paradigm of α-synuclein accumulation and clearance, find classical electrophilic Nrf2 activator tBHQ promotes endogenous Nrf2-dependent clearance astrocytes, but not cortical neurons,...
General anesthesia represents a common clinical intervention and yet can result in long-term adverse CNS effects particularly the elderly or dementia patients. Suppression of cortical activity is key feature anesthetic-induced unconscious state, with being well-described regulator pathways important for brain health. However, extent to which go beyond simple suppression neuronal incompletely understood. We found that general lowered expression genes induced by physiological vivo ,...