Heledd Haf Jarosz-Griffiths

University of Leeds · Organisational Development & Professional Learning

Introduction The apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is crucial for inflammasome assembly and activation of several inflammasomes, including NLRP3. ASC aggregates are detected in human sera post pyroptotic cell death, but their inflammasome origin remains unclear. Method This study aimed to develop...

Background Cystic fibrosis (CF) is associated with increased resting energy expenditure. However, the introduction of elexacaftor/tezacaftor/ivacaftor (ETI) has resulted in a paradigm shift in nutritional status for many people with CF, with increase body mass index and reduction in the need for nutritional support. While these changes are likely t...

The apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is crucial for inflammasome assembly and activation of several inflammasomes, including NLRP3. ASC aggregates are detected in human sera post pyroptotic cell death, but their inflammasome origin remains unclear. This study aimed to develop a method to detect A...

Inflammation is a key driver in the pathogenesis of cystic fibrosis (CF). We assessed the effectiveness of elexacaftor/tezacaftor/ivacaftor (ETI) therapy on downregulating systemic and immune cell-derived inflammatory cytokines. We also monitored the impact of ETI therapy on clinical outcome. Adults with CF, heterozygous for F508del (n = 19), were...

Background: Elexacaftor/Tezacaftor/Ivacaftor (ETI) modulator therapy is often associated with increased body mass index (BMI) in people with cystic fibrosis (CF). This is thought to reflect improved clinical stability and increased appetite and nutritional intake. We explored the change in BMI and nutritional intake following ETI modulator therapy...

Hydrogen sulfide (H2S) is gaining interest as a mammalian signalling molecule with wide ranging effects. S-sulfhydration is one mechanism that is emerging as a key post translational modification through which H2S acts. Ion channels and neuronal receptors are key target proteins for S-sulfhydration and this can influence a range of neuronal functio...

The prevalence of neurodegenerative disease has increased significantly in recent years, and with a rapidly aging global population, this trend is expected to continue. These diseases are characterised by a progressive neuronal loss in the brain or peripheral nervous system, and generally involve protein aggregation, as well as metabolic abnormalit...

Cystic fibrosis (CF) is one of the most common life-limiting recessive genetic disorders in Caucasians, caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). CF is a multi-organ disease that involves the lungs, pancreas, sweat glands, digestive and reproductive systems and several other tissues. This debilitating co...

Previously we showed that serum and monocytes from patients with CF exhibit an enhanced NLRP3-inflammasome signature with increased IL-18, IL-1β, caspase-1 activity and ASC speck release (Scambler et al., eLife 2019). Here we show that CFTR modulators down regulate this exaggerated proinflammatory response following LPS/ATP stimulation. In vitro ap...

Cystic Fibrosis (CF) is a monogenic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, resulting in defective CFTR-mediated chloride and bicarbonate transport, with dysregulation of epithelial sodium channels (ENaC). These changes alter fluid and electrolyte homeostasis and result in an exaggerated p...

Cystic Fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and results in defective CFTR-mediated chloride transport, dysregulation of epithelial sodium channels (ENaC) and exaggerated innate immune responses. We tested the hypothesis that upregulation of ENaC drives autoinflammation in this c...

Cystic Fibrosis (CF) is a recessive genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR mutations cause dysregulation of channel function with intracellular accumulation of misfolded proteins and endoplasmic reticulum (ER) stress, with activation of the IRE1α-XBP1 pathway that regulates a sub...

The cellular prion protein (PrPC) is a key neuronal receptor for amyloid-β oligomers (AβO), mediating their neurotoxicity, which contributes to the neurodegeneration in Alzheimer’s disease (AD). Similarly to the amyloid precursor protein (APP), PrPC is proteolytically cleaved from the cell surface by a disintegrin and metalloprotease, ADAM10. We hy...

Autoinflammatory syndromes are a group of disorders characterised by recurring episodes of inflammation as a result of specific defects in the innate immune system. Patients with autoinflammatory disease present with recurrent outbreaks of chronic systemic inflammation that are mediated by innate immune cells, for the most part. A number of these d...

The master pro-inflammatory cytokine, tumour necrosis factor (TNF), has been shown to modulate multiple signalling pathways, with wide-ranging downstream effects. TNF plays a vital role in the typical immune response through the regulation of a number of pathways encompassing an immediate inflammatory reaction with significant innate immune involve...

Introduction In Cystic Fibrosis (CF), infection and local hypoxia causes increased cell death, cytokine release and damage-associated molecular patterns (DAMPS) which results in hyper-inflammation. The accumulation of misfolded CFTR protein within the cell, along with loss of function leads to excessive cellular stress, defective autophagy and a di...

Cystic Fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and results in defective CFTR-mediated chloride transport, dysregulation of epithelial sodium channels (ENaC) and exaggerated innate immune responses. We tested the hypothesis that upregulation of ENaC drives autoinflammation in this c...

Cellular stress is one of the main physiological activators of the unfolded protein response (UPR) in eukaryotic cells. These cells are under constant environmental and metabolic challenges, which may activate evolutionarily conserved mechanisms, such as the UPR, to reconstitute intracellular homeostasis. When intracellular equilibrium cannot be ac...

Introduction: Synapse loss is the structural correlate of the cognitive decline indicative of dementia. In the brains of Alzheimer's disease sufferers, amyloid β (Aβ) peptides aggregate to form senile plaques but as soluble peptides are toxic to synapses. We previously demonstrated that Aβ induces Dickkopf-1 (Dkk1), which in turn activates the Wnt–...

Introduction: Synapse loss is the basis of the cognitive decline indicative of dementia. In the brains of Alzheimer's disease (AD) sufferer's amyloid beta (Aβ) peptides aggregate to form senile plaques but as soluble peptides that are toxic to synapses. We previously demonstrated that Aβ induces Dickkopf-1 (Dkk1), which in turn activates the Wnt-p...

Alzhiemer’s disease (AD) is driven by β-amyloid (Aβ), which initiates a cascade of events resulting in abnormal phosphorylation of tau and cognitive impairment. Soluble Aβ oligomers are held to be toxic form of Aβ. Performance in the Novel Object Recognition (NOR) task has been found to be as effective as the Morris Water Maze for evaluating cognit...

Several different receptor proteins have been identified that bind monomeric, oligomeric, or fibrillar forms of amyloid-β (Aβ). "Good" receptors internalize Aβ or promote its transcytosis out of the brain, whereas "bad" receptors bind oligomeric forms of Aβ that are largely responsible for the synaptic loss, memory impairments, and neurotoxicity th...

Several different receptor proteins have been identified that bind monomeric, oligomeric or fibrillar forms of amyloid-β (Aβ). ″Good″ receptors internalise Aβ or promote its transcytosis out of the brain, whereas ″bad″ receptors bind oligomeric forms of Aβ that are largely responsible for the synaptic loss, memory impairments and neurotoxicity whic...

Amyloid beta (Aβ) is thought to initiate the cascade resulting in the abnormal phosphorylation of tau in Alzhiemer’s disease (AD). It has been shown soluble Aβ oligomers, rather than the plaques, are the toxic species in AD, and therefore the blockade of this oligomer action could result in prevention of the disease. Aβ has been shown to bind with...

[Poster]

Heme oxygenase-1 (HO-1), an inducible enzyme up-regulated in Alzheimer's disease, catabolises heme to biliverdin, Fe(2+) and carbon monoxide (CO). CO can protect neurones from oxidative stress-induced apoptosis by inhibiting Kv2.1 channels, which mediates cellular K(+) efflux as an early step in the apoptotic cascade. Since apoptosis contributes to...

Dysregulation of neuronal zinc homeostasis plays a major role in many processes related to brain aging and neurodegenerative diseases, including Alzheimer's disease (AD). Yet, despite the critical role of zinc in neuronal function, the cellular mechanisms underpinning its homeostatic control are far from clear. We reported that the cellular prion p...

Alzheimer's disease (AD) is the most common form of dementia, with over 37 million sufferers worldwide and a global cost of over $600 billion. There is currently no cure for AD and no reliable method of diagnosis other than post-mortem brain examination. The development of a point-of-care test for AD is an urgent requirement in order to provide ear...

Zinc, the most abundant trace metal in the brain, has numerous functions in health and disease. It is released into the synaptic cleft alongside glutamate and this connection between zinc and glutamatergic neurotransmission allows the ion to modulate overall excitability of the brain and influence synaptic plasticity. To maintain healthy synapses,...

Soluble oligomers of the amyloid-β (Aβ) peptide cause neurotoxicity, synaptic dysfunction and memory impairments which underlie Alzheimers disease (AD). The cellular prion protein (PrPC) was recently identified as a high-affinity neuronal receptor for Aβ oligomers. We report that fibrillar Aβ oligomers recognised by the OC antibody, which have been...

Zinc is released into the synaptic cleft upon exocytotic stimuli, although the mechanism for its reuptake into neurons is unresolved. Here we show that the cellular prion protein enhances the uptake of zinc into neuronal cells. This prion-protein-mediated zinc influx requires the octapeptide repeats and amino-terminal polybasic region in the prion...

Supplementary Figures S1-S4, Supplementary Methods and Supplementary Reference

Alzheimer disease (AD) is characterized by the amyloidogenic processing of the amyloid precursor protein (APP), culminating in the accumulation of amyloid-β peptides in the brain. The enzymatic action of the β-secretase, BACE1 is the rate-limiting step in this amyloidogenic processing of APP. BACE1 cleavage of wild-type APP (APPWT) is inhibited by...

In Alzheimer disease amyloid-β (Aβ) peptides derived from the amyloid precursor protein (APP) accumulate in the brain. Cleavage of APP by the β-secretase BACE1 is the rate-limiting step in the production of Aβ. We have reported previously that the cellular prion protein (PrP(C)) inhibited the action of BACE1 toward human wild type APP (APP(WT)) in...

1. In vivo clearance predictions from in vitro assays require scaling factors to relate the concentrations of hepatocytes or microsomal protein to the intact liver. 2. The aims were to measure the variability in scaling factors for Wistar rat and beagle dog for which the literature is particularly scarce and determine any sex differences. 3. Scalin...

The amyloid beta (Abeta) peptide is critical to the development of Alzheimer's disease (AD), the major neurodegenerative disease of the elderly for which there is currently no cure. To review the literature on emerging treatments and potential therapeutic strategies for AD. Available published literature and information from pharmaceutical companie...