Pharmacology and Therapeutics - Research Publications
Permanent URI for this collection
Search Results
1 - 10 of 27
-
ItemType-I interferons in Parkinson's disease: innate inflammatory response drives fate of neurons in model of degenerative brain disorder: An editorial comment on 'Type-I interferons mediate the neuroinflammatory response and neurotoxicity induced by rotenone'(WILEY, 2017-04)Read the commented article 'Type-I interferons mediate the neuroinflammatory response and neurotoxicity induced by rotenone' on page 75.
-
ItemNo Preview AvailableFailure of Autophagy-Lysosomal Pathways in Rod Photoreceptors Causes the Early Retinal Degeneration Phenotype Observed in Cln6nclf Mice(ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2018-10)PURPOSE: Vision loss caused by photoreceptor death represents one of the first symptoms in neuronal ceroid lipofuscinosis, a condition characterized by accumulation of intracellular waste. Cln6nclf mice have a naturally occurring mutation in ceroid-lipofuscinosis neuronal (CLN) protein 6 and are a model of this disorder. In order to identify the effect intracellular waste (lipofuscin) accumulation plays in driving retinal degeneration, the time course of degeneration was carefully characterized functionally using the electroretinogram and structurally using histology. METHODS: Cln6nclf and C57BL/6J, wild-type, mice were studied at postnatal day 18 (P18), P30, P60, P120, and P240, and retinal degeneration was correlated with changes in the retinal pigment epithelial (RPE) and neuronal autophagy-lysosomal pathways using super-resolution microscopy. RESULTS: In Cln6nclf mice there was significant loss of rod photoreceptor function at P18, prior to photoreceptor nuclei loss at P60. In contrast, cone pathway function was not affected until P240. The loss of rod photoreceptor function correlated with significant disruption of the autophagy-lysosomal degradation pathways within photoreceptors, but not in the RPE or other retinal neurons. Additionally, there was cytosolic accumulation of P62 and undigested mitochondrial-derived, ATP synthase subunit C in the photoreceptor layers of Cln6nclf mice at P30. CONCLUSIONS: These results suggest that rod photoreceptors have an increased sensitivity to disturbances in the autophagy-lysosomal pathway and the subsequent failure of mitochondrial turnover, relative to other retinal cells. It is likely that primary failure of the rod photoreceptors rather than the RPE or other retinal neurons underlies the early visual dysfunction that occurs in the Cln6nclf mouse model.
-
ItemMetal-deficient SOD1 in amyotrophic lateral sclerosis(SPRINGER, 2015-05)Mutations to the ubiquitous antioxidant enzyme Cu/Zn superoxide dismutase (SOD1) were the first established genetic cause of the fatal, adult-onset neurodegenerative disease amyotrophic lateral sclerosis (ALS). It is widely accepted that these mutations do not cause ALS via a loss of antioxidant function, but elucidating the alternate toxic gain of function has proven to be elusive. Under physiological conditions, SOD1 binds one copper ion and one zinc ion per monomer to form a highly stable and functional homodimer, but there is now ample evidence to indicate aberrant persistence of SOD1 in an intermediate metal-deficient state may contribute to the protein's involvement in ALS. This review briefly discusses some of the data to support a role for metal-deficient SOD1 in the development of ALS and some of the outcomes from drug development studies that have aimed to modify the symptoms of ALS by targeting the metal state of SOD1. The implications for the metal state of SOD1 in cases of sporadic ALS that do not involve mutant SOD1 are also discussed.
-
ItemIncreased metal content in the TDP-43A315T transgenic mouse model of frontotemporal lobar degeneration and amyotrophic lateral sclerosis(FRONTIERS MEDIA SA, 2014-02-11)Disrupted metal homeostasis is a consistent feature of neurodegenerative disease in humans and is recapitulated in mouse models of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) and neuronal ceriod lipofuscinosis. While the definitive pathogenesis of neurodegenerative disease in humans remains to be fully elucidated, disease-like symptoms in the mouse models are all driven by the presence or over-expression of a putative pathogenic protein, indicating an in vivo relationship between expression of these proteins, disrupted metal homeostasis and the symptoms of neuronal failure. Recently it was established that mutant TAR DNA binding protein-43 (TDP-43) is associated with the development of frontotemporal lobar degeneration and ALS. Subsequent development of transgenic mice that express human TDP-43 carrying the disease-causing A315T mutation has provided new opportunity to study the underlying mechanisms of TDP-43-related neurodegenerative disease. We assessed the cognitive and locomotive phenotype of TDP-43 (A315T) mice and their wild-type littermates and also assessed bulk metal content of brain and spinal cord tissues. Metal levels in the brain were not affected by the expression of mutant TDP-43, but zinc, copper, and manganese levels were all increased in the spinal cords of TDP-43 (A315T) mice when compared to wild-type littermates. Performance of the TDP-43 (A315T) mice in the Y-maze test for cognitive function was not significantly different to wild-type mice. By contrast, performance of the TDP-43 (A315T) in the rotarod test for locomotive function was consistently worse than wild-type mice. These preliminary in vivo data are the first to show that expression of a disease-causing form of TDP-43 is sufficient to disrupt metal ion homeostasis in the central nervous system. Disrupted metal ion homeostasis in the spinal cord but not the brain may explain why the TDP-43 (A315T) mice show symptoms of locomotive decline and not cognitive decline.
-
ItemNeuroinflammation and copper in Alzheimer's disease.(Hindawi Limited, 2013)Inflammation is the innate immune response to infection or tissue damage. Initiation of proinflammatory cascades in the central nervous system (CNS) occurs through recognition of danger associated molecular patterns by cognate immune receptors expressed on inflammatory cells and leads to rapid responses to remove the danger stimulus. The presence of activated microglia and astrocytes in the vicinity of amyloid plaques in the brains of Alzheimer's disease (AD) patients and mouse models implicates inflammation as a contributor to AD pathogenesis. Activated microglia play a critical role in amyloid clearance, but chronic deregulation of CNS inflammatory pathways results in secretion of neurotoxic mediators that ultimately contribute to neurodegeneration in AD. Copper (Cu) homeostasis is profoundly affected in AD, and accumulated extracellular Cu drives A β aggregation, while intracellular Cu deficiency limits bioavailable Cu required for CNS functions. This review presents an overview of inflammatory events that occur in AD in response to A β and highlights recent advances on the role of Cu in modulation of beneficial and detrimental inflammatory responses in AD.
-
ItemIncreased Zinc and Manganese in Parallel with Neurodegeneration, Synaptic Protein Changes and Activation of Akt/GSK3 Signaling in Ovine CLN6 Neuronal Ceroid Lipofuscinosis(PUBLIC LIBRARY SCIENCE, 2013-03-14)Mutations in the CLN6 gene cause a variant late infantile form of neuronal ceroid lipofuscinosis (NCL; Batten disease). CLN6 loss leads to disease clinically characterized by vision impairment, motor and cognitive dysfunction, and seizures. Accumulating evidence suggests that alterations in metal homeostasis and cellular signaling pathways are implicated in several neurodegenerative and developmental disorders, yet little is known about their role in the NCLs. To explore the disease mechanisms of CLN6 NCL, metal concentrations and expression of proteins implicated in cellular signaling pathways were assessed in brain tissue from South Hampshire and Merino CLN6 sheep. Analyses revealed increased zinc and manganese concentrations in affected sheep brain in those regions where neuroinflammation and neurodegeneration first occur. Synaptic proteins, the metal-binding protein metallothionein, and the Akt/GSK3 and ERK/MAPK cellular signaling pathways were also altered. These results demonstrate that altered metal concentrations, synaptic protein changes, and aberrant modulation of cellular signaling pathways are characteristic features in the CLN6 ovine form of NCL.
-
ItemBiometals in rare neurodegenerative disorders of childhood(FRONTIERS MEDIA SA, 2013-03-25)Copper, iron, and zinc are just three of the main biometals critical for correct functioning of the central nervous system (CNS). They have diverse roles in many functional processes including but not limited to enzyme catalysis, protein stabilization, and energy production. The range of metal concentrations within the body is tightly regulated and when the balance is perturbed, debilitating effects ensue. Homeostasis of brain biometals is mainly controlled by various metal transporters and metal sequestering proteins. The biological roles of biometals are vastly reviewed in the literature with a large focus on the connection to neurological conditions associated with ageing. Biometals are also implicated in a variety of debilitating inherited childhood disorders, some of which arise soon following birth or as the child progresses into early adulthood. This review acts to highlight what we know about biometals in childhood neurological disorders such as Wilson's disease (WD), Menkes disease (MD), neuronal ceroid lipofuscinoses (NCLs), and neurodegeneration with brain iron accumulation (NBIA). Also discussed are some of the animal models available to determine the pathological mechanisms in these childhood disorders, which we hope will aid in our understanding of the role of biometals in disease and in attaining possible therapeutics in the future.
-
ItemEditorial: Metals and neurodegeneration: restoring the balance(FRONTIERS RESEARCH FOUNDATION, 2015-07-02)
-
ItemUrban air particulate matter induces mitochondrial dysfunction in human olfactory mucosal cells(BMC, 2020-06-01)BACKGROUND: The adverse effects of air pollutants including particulate matter (PM) on the central nervous system is increasingly reported by epidemiological, animal and post-mortem studies in the last decade. Oxidative stress and inflammation are key consequences of exposure to PM although little is known of the exact mechanism. The association of PM exposure with deteriorating brain health is speculated to be driven by PM entry via the olfactory system. How air pollutants affect this key entry site remains elusive. In this study, we investigated effects of urban size-segregated PM on a novel cellular model: primary human olfactory mucosal (hOM) cells. RESULTS: Metabolic activity was reduced following 24-h exposure to PM without evident signs of toxicity. Results from cytometric bead array suggested a mild inflammatory response to PM exposure. We observed increased oxidative stress and caspase-3/7 activity as well as perturbed mitochondrial membrane potential in PM-exposed cells. Mitochondrial dysfunction was further verified by a decrease in mitochondria-dependent respiration. Transient suppression of the mitochondria-targeted gene, neuronal pentraxin 1 (NPTX1), was carried out, after being identified to be up-regulated in PM2.5-1 treated cells via RNA sequencing. Suppression of NPTX1 in cells exposed to PM did not restore mitochondrial defects resulting from PM exposure. In contrast, PM-induced adverse effects were magnified in the absence of NPTX1, indicating a critical role of this protein in protection against PM effects in hOM cells. CONCLUSION: Key mitochondrial functions were perturbed by urban PM exposure in a physiologically relevant cellular model via a mechanism involving NPTX1. In addition, inflammatory response and early signs of apoptosis accompanied mitochondrial dysfunction during exposure to PM. Findings from this study contribute to increased understanding of harmful PM effects on human health and may provide information to support mitigation strategies targeted at air pollution.
-
ItemAltered Brain Endothelial Cell Phenotype from a Familial Alzheimer Mutation and Its Potential Implications for Amyloid Clearance and Drug Delivery(CELL PRESS, 2020-05-12)The blood-brain barrier (BBB) presents a barrier for circulating factors, but simultaneously challenges drug delivery. How the BBB is altered in Alzheimer disease (AD) is not fully understood. To facilitate this analysis, we derived brain endothelial cells (iBECs) from human induced pluripotent stem cells (hiPSCs) of several patients carrying the familial AD PSEN1 mutation. We demonstrate that, compared with isogenic PSEN1 corrected and control iBECs, AD-iBECs exhibit altered tight and adherens junction protein expression as well as efflux properties. Furthermore, by applying focused ultrasound (FUS) that transiently opens the BBB and achieves multiple therapeutic effects in AD mouse models, we found an altered permeability to 3-5 kDa dextran as a model cargo and the amyloid-β (Aβ) peptide in AD-iBECs compared with control iBECs. This presents human-derived in vitro models of the BBB as a valuable tool to understand its role and properties in a disease context, with possible implications for drug delivery.