Conforti L.,University of Nottingham |
Gilley J.,Babraham Institute |
Coleman M.P.,Babraham Institute
Nature Reviews Neuroscience | Year: 2014
Axon degeneration is a prominent early feature of most neurodegenerative disorders and can also be induced directly by nerve injury in a process known as Wallerian degeneration. The discovery of genetic mutations that delay Wallerian degeneration has provided insight into mechanisms underlying axon degeneration in disease. Rapid Wallerian degeneration requires the pro-degenerative molecules SARM1 and PHR1. Nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) is essential for axon growth and survival. Its loss from injured axons may activate Wallerian degeneration, whereas NMNAT overexpression rescues axons from degeneration. Here, we discuss the roles of these and other proposed regulators of Wallerian degeneration, new opportunities for understanding disease mechanisms and intriguing links between Wallerian degeneration, innate immunity, synaptic growth and cell death. © 2014 Macmillan Publishers Limited.
Veldhoen M.,Babraham Institute |
Brucklacher-Waldert V.,Babraham Institute
Nature Reviews Immunology | Year: 2012
The function of the gastrointestinal tract relies on a monolayer of epithelial cells, which are essential for the uptake of nutrients. The fragile lining requires protection against insults by a diverse array of antigens. This is accomplished by the mucosa-associated lymphoid tissues of the gastrointestinal tract, which constitute a highly organized immune organ. In this Review, we discuss several recent findings that provide a compelling link between dietary compounds and the organization and maintenance of immune tissues and lymphocytes in the intestine. We highlight some of the molecular players involved, in particular ligand-activated nuclear receptors in lymphoid cells. © 2012 Macmillan Publishers Limited. All rights reserved.
Coleman M.P.,Babraham Institute |
Freeman M.R.,University of Massachusetts Medical School
Annual Review of Neuroscience | Year: 2010
Traditionally, researchers have believed that axons are highly dependent on their cell bodies for long-term survival. However, recent studies point to the existence of axon-autonomous mechanism(s) that regulate rapid axon degeneration after axotomy. Here, we review the cellular and molecular events that underlie this process, termed Wallerian degeneration. We describe the biphasic nature of axon degeneration after axotomy and our current understanding of how Wld San extraordinary protein formed by fusing a Ube4b sequence to Nmnat1acts to protect severed axons. Interestingly, the neuroprotective effects of WldS span all species tested, which suggests that there is an ancient, WldS-sensitive axon destruction program. Recent studies with WldS also reveal that Wallerian degeneration is genetically related to several dying back axonopathies, thus arguing that Wallerian degeneration can serve as a useful model to understand, and potentially treat, axon degeneration in diverse traumatic or disease contexts. © 2010 by Annual Reviews. All rights reserved.
Agency: European Commission | Branch: H2020 | Program: RIA | Phase: PHC-03-2015 | Award Amount: 5.70M | Year: 2016
Hepatocellular carcinoma (HCC) is the most common liver malignancy, with an estimated 750,000 new cases and 695,000 deaths per year, rating third in incidence and mortality in the world. Whilst incidence and mortality for other cancers are declining, HCC represents an increasing public health problem in Europe with men having a higher incidence than women. Several liver diseases lead to HCC and become per definition co-morbidities, such as nonalcoholic steatohepatitis (NASH) or hepatitis B and C virus infection. Most patients die within one year of diagnosis and treatment failure reflects the heterogeneous nature of this tumour, highlighting the need to identify common and co-morbidity specific disease pathways for individualized therapy. HEP-CAR will focus on three leading HCC associated co-morbidities, specifically NASH and hepatitis B and C infection. Non-biased genetic and lipidomic screens will define cellular pathways that are deregulated in HCC and the impact of co-morbidities and gender. Next to established patient cohorts, several in vitro and in vivo models are available to evaluate the role of co-morbidities as drivers of host oncogenic pathways and to provide much needed pre-clinical models for mechanistic studies and future drug screening. We will develop new approaches to study the impact of co-morbidities on HCC immunobiology, ranging from state-of-art tissue explant models to novel humanized mouse models. The aim of HEP-CAR is to define host pathways that impact HCC pathogenesis and to assess their role in different co-morbidities and treatment responses. The research and clinical excellence will be combined with the knowledge transfer and communication competence of leading organizations such as the European Association for the Study of the Liver (EASL) and the European Liver Patients Association (ELPA). Thus, HEP-CAR will generate tangible and sustained improvements in the understanding, prevention and management of HCC for all European citizens.
Berridge M.J.,Babraham Institute
Biochemical Society Transactions | Year: 2012
A wide range of Ca 2+ signalling systems deliver the spatial and temporal Ca 2+ signals necessary to control the specific functions of different cell types. Release of Ca 2+ by InsP 3 (inositol 1,4,5-trisphosphate) plays a central role in many of these signalling systems. Ongoing transcriptional processes maintain the integrity and stability of these cell-specific signalling systems. However, these homoeostatic systems are highly plastic and can undergo a process of phenotypic remodelling, resulting in the Ca 2+ signals being set either too high or too low. Such subtle dysregulation of Ca 2+ signals have been linked to some of the major diseases in humans such as cardiac disease, schizophrenia, bipolar disorder and Alzheimer's disease. © The Authors Journal compilation © 2012 Biochemical Society.
Fearnley C.J.,Babraham Institute
Cold Spring Harbor perspectives in biology | Year: 2011
Calcium (Ca(2+)) is a critical regulator of cardiac myocyte function. Principally, Ca(2+) is the link between the electrical signals that pervade the heart and contraction of the myocytes to propel blood. In addition, Ca(2+) controls numerous other myocyte activities, including gene transcription. Cardiac Ca(2+) signaling essentially relies on a few critical molecular players--ryanodine receptors, voltage-operated Ca(2+) channels, and Ca(2+) pumps/transporters. These moieties are responsible for generating Ca(2+) signals upon cellular depolarization, recovery of Ca(2+) signals following cellular contraction, and setting basal conditions. Whereas these are the central players underlying cardiac Ca(2+) fluxes, networks of signaling mechanisms and accessory proteins impart complex regulation on cardiac Ca(2+) signals. Subtle changes in components of the cardiac Ca(2+) signaling machinery, albeit through mutation, disease, or chronic alteration of hemodynamic demand, can have profound consequences for the function and phenotype of myocytes. Here, we discuss mechanisms underlying Ca(2+) signaling in ventricular and atrial myocytes. In particular, we describe the roles and regulation of key participants involved in Ca(2+) signal generation and reversal.
Le Novere N.,Babraham Institute
Nature Reviews Genetics | Year: 2015
Behaviours of complex biomolecular systems are often irreducible to the elementary properties of their individual components. Explanatory and predictive mathematical models are therefore useful for fully understanding and precisely engineering cellular functions. The development and analyses of these models require their adaptation to the problems that need to be solved and the type and amount of available genetic or molecular data. Quantitative and logic modelling are among the main methods currently used to model molecular and gene networks. Each approach comes with inherent advantages and weaknesses. Recent developments show that hybrid approaches will become essential for further progress in synthetic biology and in the development of virtual organisms. © 2015 Macmillan Publishers Limited.
Okkenhaug K.,Babraham Institute
Annual Review of Immunology | Year: 2013
Phosphoinositide 3-kinases (PI3Ks) control many important aspects of immune cell development, differentiation, and function. Mammals have eight PI3K catalytic subunits that are divided into three classes based on similarities in structure and function. Specific roles for the class I PI3Ks have been broadly investigated and are relatively well understood, as is the function of their corresponding phosphatases. More recently, specific roles for the class II and class III PI3Ks have emerged. Through vertebrate evolution and in parallel with the evolution of adaptive immunity, there has been a dramatic increase not only in the genes for PI3K subunits but also in genes for phosphatases that act on 3-phosphoinositides and in 3-phosphoinositide-binding proteins. Our understanding of the PI3Ks in immunity is guided by fundamental discoveries made in simpler model organisms as well as by appreciating new adaptations of this signaling module in mammals in general and in immune cells in particular. © Copyright 2013 by Annual Reviews. All rights reserved.
Berridge M.J.,Babraham Institute
Journal of Physiology | Year: 2014
Alzheimer's disease (AD) begins with a decline in cognition followed by neuronal cell death and dementia. These changes have been linked to a deregulation of Ca2+ signalling caused by a progressive increase in the resting level of Ca2+, which may influence cognition by interfering with the rhythm rheostat that controls the sleep/wake cycle. The rise in resting levels of Ca2+ may not alter the processes of memory acquisition during consciousness (gamma and theta rhythms), but may duplicate some of the events that occur during the slow oscillations responsible for the twin processes of memory consolidation and memory erasure that occur during sleep. The persistent elevation in the resting level of Ca2+ induced by an accumulation of amyloid β (Aβ) oligomers duplicates a similar small global elevation normally restricted to the period of slow oscillations when memories are erased during sleep. In AD, such a rapid erasure of memories soon after they are acquired during the wake period means that they are not retained for consolidation during sleep. The Aβ deregulates Ca2+ signalling through direct effects on the neurons and indirectly by inducing inflammatory responses in the microglia and astrocytes. Some of these deleterious effects of Aβ may be alleviated by vitamin D. © 2013 The Physiological Society.
Agency: GTR | Branch: BBSRC | Program: | Phase: Research Grant | Award Amount: 327.03K | Year: 2017
The cells in our body are constantly exposed to chemical and physical stress and accumulate a lifetime of damage to proteins, DNA and various key sub-cellular structures (organelles). It is vital that cells are able to respond appropriately to this damage; failure to do so progressively undermines cellular fitness contributing to age-related declines in cell and tissue function that underpin the normal ageing process and can contribute to age-related diseases such as cancer and dementia. One way that cells respond to stress is to increase the abundance of enzymes that detoxify the cell by removing potentially harmful chemicals. When a cell receives a stress signal the genes that code for detoxifying enzymes are read by transcription factors, discrete proteins that bind to DNA and transcribe the DNA information into RNA molecules, which are in turn translated into the relevant proteins. One such transcription factor, called NRF2, coordinates cellular responses to oxidative stress. Another way in which cells deal with cellular damage is through a process called autophagy (self eating) in which damaged proteins are targeted to cellular recycling centres (called autophagosomes), where they are broken down to their raw materials, which can then be re-used. This process of autophagy requires cargo receptors, which bind to damaged proteins and transport them to the recycling centre for autophagy. These complex processes are orchestrated by signalling pathways within cells that involve cascades of enzymes called protein kinases. These enzymes tag other proteins with a phosphate group (a process called phosphorylation) and this changes the activity, abundance or localisation of the protein. The tagged protein is referred to as the substrate of the protein kinase enzyme. This project concerns two protein kinases, called DYRK1B and DYRK2, and a specific cargo receptor called p62 or sequestosome-1; here well call it p62. Our new results point to a link between the DYRKs and p62 in coordinating how cells respond to stress and damage:- 1. p62 acts as a scaffold to coordinate the activation of the NRF2 transcription factor. We have now discovered that DYRK1B controls the expression of detoxifying enzymes that are known to be targets of NRF2 suggesting that DYRK1B may control activation of NRF2. 2. p62 acts as a cargo receptor for damaged proteins, transporting them to recycling centres for autophagy. It has also been shown that p62 can shuttle in and out of the cell nucleus to collect damaged nuclear proteins for autophagy. This nuclear shuttling requires phosphorylation of p62 but the kinase responsible for this has remained a mystery. We have now discovered for the first time that p62 is phosphorylated by DYRK1B and DYRK2; we propose that this sends p62 into the nucleus to help collect damaged nuclear proteins. 3. p62 coordinates activation of a protein kinase enzyme called mTOR when cells are starved of nutrients. Indeed, mTOR is a critical regulator of lifelong health and controls the lifespan of organisms such as worms, flies, mice and possibly man. Regulation of mTOR by nutrients takes place at specific organelles called lysosomes. However, the phosphorylation of p62 may take it away from lysosomes to the nucleus. Indeed, we find that DYRK2 and p62 co-locate in cells at aggresomes - sites of damaged proteins, consistent with the cargo function of p62. It is not known what effect this re-location of p62 has on nutrient signalling via mTOR at lysosomes. In this study we will define how the DYRKs regulate p62 to coordinate cellular responses to stress and damage. This work is critical to understanding how stress contributes to normal ageing but may also have implications for diseases of old age (dementia, cancer); thus, our results may have wider impacts and we will work with scientists in these areas to progress this.