A5029498999- Neuroscience and Neuropharmacology Research
- Sphingolipid Metabolism and Signaling
- Neuroinflammation and Neurodegeneration Mechanisms
- Alzheimer's disease research and treatments
- Multiple Sclerosis Research Studies
- Receptor Mechanisms and Signaling
- Ion channel regulation and function
- Lysosomal Storage Disorders Research
- Lipid Membrane Structure and Behavior
- Cholesterol and Lipid Metabolism
- Protein Kinase Regulation and GTPase Signaling
- Neurogenesis and neuroplasticity mechanisms
- Cellular transport and secretion
- Chemokine receptors and signaling
- Memory and Neural Mechanisms
- Hippo pathway signaling and YAP/TAZ
- Tryptophan and brain disorders
- RNA Interference and Gene Delivery
- Endoplasmic Reticulum Stress and Disease
- Ubiquitin and proteasome pathways
- Parkinson's Disease Mechanisms and Treatments
- PARP inhibition in cancer therapy
- Nuclear Receptors and Signaling
- Immune Cell Function and Interaction
- Nicotinic Acetylcholine Receptors Study
Trinity College Dublin
2015-2024
Arizona State University
2012
Milbank Memorial Fund
2010-2011
Novartis (Switzerland)
2001-2010
Novartis Institutes for BioMedical Research
2004-2010
University College Cork
2007-2009
Novartis (China)
2008
University of Bristol
1995-2004
Medical Research Council
2002-2004
Kyoto University
1999-2004
Peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) is a highly regulated transcriptional coactivator that coordinates energy metabolism in mammals. Misregulation of PGC-1α has been implicated the pathogenesis several human diseases, including diabetes, obesity, and neurological disorders. We identified SCF Cdc4 as an E3 ubiquitin ligase regulates through ubiquitin-mediated proteolysis. contains two phosphodegrons bind when phosphorylated by Glycogen Synthase Kinase...
α-Synuclein (αSN) in human is tightly linked both neuropathologically and genetically to Parkinson's disease (PD) related disorders. Disease-causing properties vivo of the wildtype mouse ortholog (mαSN), which carries a threonine at position 53 like A53T mutant version that PD, were never reported. To this end we generated lines express mαSN central neurons levels reaching up six-fold compared endogenous mαSN. Unlike transgenic mice expressing or forms αSN, these showed pronounced ubiquitin...
BAF312 (Siponimod) is a dual agonist at the sphingosine-1 phosphate receptors, S1PR1 and S1PR5. This drug currently undergoing clinical trials for treatment of secondary progressive multiple sclerosis (MS). Here, we investigated effects on isolated astrocyte microglia cultures as well in slice culture models demyelination. Mouse human astrocytes were treated with S1PR modulators changes levels pERK, pAkt, calcium signalling internalization cytokine was using Western blotting,...
Astrocytes are important for information processing in the brain and they achieve this by fine-tuning neuronal communication via continuous uptake release of biochemical modulators neurotransmission synaptic plasticity. Often overlooked their functions mechanosensation. Indeed, astrocytes can detect pathophysiological changes mechanical properties injured, ageing, or degenerating tissue. We have recently shown that surrounding mechanically-stiff amyloid plaques upregulate mechanosensitive...
The G-protein-coupled metabotropic glutamate receptor subtype 7a (mGluR7a) is a member of group III receptors that plays an important role as presynaptic in regulating transmitter release at glutamatergic synapses. Here we report the protein interacting with C-kinase (PICK1) binds to C terminus (ct) mGluR7a. In yeast two-hybrid system, extreme ct mGluR7a was shown interact PSD-95/Discs large/ZO-1 (PDZ) domain PICK1. Pull-down assays indicated PICK1 retained by glutathione...
Abstract Sphingosine‐1‐phosphate (S1P) receptors are widely expressed in the central nervous system where they thought to regulate glia cell function. The phosphorylated version of fingolimod/FTY720 (FTY720P) is active on a broad spectrum S1P and parent compound currently phase III clinical trials for treatment multiple sclerosis. Here, we aimed identify which type(s) receptor(s) targeted by FTY720P. Using calcium imaging mixed cultures from embryonic rat cortex show that astrocytes major...
Sphingosine 1-phosphate receptors (S1PR) are G protein-coupled and compose a family with five subtypes, S1P1R-S1P5R. The drug Gilenya® (Novartis, Basel, Switzerland) (Fingolimod; FTY720) targets S1PRs was the first oral therapy for patients relapsing-remitting multiple sclerosis (MS). phosphorylated form of FTY720 (pFTY720) binds causing initial agonism, then subsequent receptor internalization functional antagonism. Internalization S1P1R attenuates sphingosine (S1P)-mediated egress...
A defining pathophysiological hallmark of Alzheimer's disease (AD) is the amyloid plaque; an extracellular deposit aggregated fibrillar Aβ
The family of interleukin 17 receptors (IL17Rs), subtypes IL17RA-IL17RE, is targeted by the group pro-inflammatory IL17 cytokines (IL17A-F) and moreover newly developed anti-IL17A antibody secukinumab (AIN457) has shown promise in Phase II trials multiple sclerosis. Here, we show that human astrocytes, isolated from a fetal cerebral cortex, express IL17RA IL17RC vitro treatment with IL17A increases protein levels IL6 which enhanced presence TNFα, as determined homogeneous time resolved...
Piezo1 is a mechanosensitive ion channel that facilitates the translation of extracellular mechanical cues to intracellular molecular signaling cascades through process termed, mechanotransduction. In central nervous system (CNS), mechanically gated channels are important regulators neurodevelopmental processes such as axon guidance, neural stem cell differentiation, and myelination axons by oligodendrocytes. Here, we present evidence pharmacologically mediated overactivation negatively...
The human genome encodes seven intramembrane-cleaving GXGD aspartic proteases. These are the two presenilins that activate signaling molecules and implicated in Alzheimer's disease, signal peptide peptidase (SPP), required for immune surveillance, four SPP-like candidate proteases (SPPLs), of unknown function. Here we describe a comparative analysis topologies SPP its homologues, SPPL2a, -2b, -2c, -3. We demonstrate their N-terminal extensions located extracellular space and, except SPPL3,...
The G protein‐coupled receptor EBI2 (Epstein–Barr virus‐induced gene 2) is activated by 7 α , 25‐dihydroxycholesterol (7 25HC) and plays a role in T cell‐dependant antibody response B cell migration. Aberrant signaling implicated range of autoimmune disorders however its the CNS remains unknown. Here we characterize functional GLIA cells using primary human astrocytes knockout animals. We find mouse express enzymes necessary for synthesis degradation 25HC. In astrocytes, activation...