Lynn Bedford
University of Nottingham
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Featured researches published by Lynn Bedford.
Nature Reviews Drug Discovery | 2011
Lynn Bedford; James Lowe; Lawrence R. Dick; R. John Mayer; James E. Brownell
The ubiquitin–proteasome system (UPS) and ubiquitin-like protein (UBL) conjugation pathways are integral to cellular protein homeostasis. The growing recognition of the fundamental importance of these pathways to normal cell function and in disease has prompted an in-depth search for small-molecule inhibitors that selectively block the function of these pathways. However, our limited understanding of the molecular mechanisms and biological consequences of UBL conjugation is a significant hurdle to identifying drug-like inhibitors of enzyme targets within these pathways. Here, we highlight recent advances in understanding the role of some of these enzymes and how these new insights may be the key to developing novel therapeutics for diseases including immuno-inflammatory disorders, cancer, infectious diseases, cardiovascular disease and neurodegenerative disorders.
The Journal of Neuroscience | 2008
Lynn Bedford; David Hay; Anny Devoy; Simon Paine; Des G. Powe; Rashmi Seth; Trevor Gray; Ian A. Topham; Kevin C.F. Fone; Nooshin Rezvani; Maureen Mee; Tim Soane; Robert Layfield; Paul W. Sheppard; Ted Ebendal; Dmitry Usoskin; James Lowe; R. John Mayer
Ubiquitin-positive intraneuronal inclusions are a consistent feature of the major human neurodegenerative diseases, suggesting that dysfunction of the ubiquitin proteasome system is central to disease etiology. Research using inhibitors of the 20S proteasome to model Parkinsons disease is controversial. We report for the first time that specifically 26S proteasomal dysfunction is sufficient to trigger neurodegenerative disease. Here, we describe novel conditional genetic mouse models using the Cre/loxP system to spatially restrict inactivation of Psmc1 (Rpt2/S4) to neurons of either the substantia nigra or forebrain (e.g., cortex, hippocampus, and striatum). PSMC1 is an essential subunit of the 26S proteasome and Psmc1 conditional knock-out mice display 26S proteasome depletion in targeted neurons, in which the 20S proteasome is not affected. Impairment of specifically ubiquitin-mediated protein degradation caused intraneuronal Lewy-like inclusions and extensive neurodegeneration in the nigrostriatal pathway and forebrain regions. Ubiquitin and α-synuclein neuropathology was evident, similar to human Lewy bodies, but interestingly, inclusion bodies contained mitochondria. We support this observation by demonstrating mitochondria in an early form of Lewy body (pale body) from Parkinsons disease patients. The results directly confirm that 26S dysfunction in neurons is involved in the pathology of neurodegenerative disease. The model demonstrates that 26S proteasomes are necessary for normal neuronal homeostasis and that 20S proteasome activity is insufficient for neuronal survival. Finally, we are providing the first reproducible genetic platform for identifying new therapeutic targets to slow or prevent neurodegeneration.
Trends in Cell Biology | 2010
Lynn Bedford; Simon Paine; Paul W. Sheppard; R. John Mayer; Jeroen Roelofs
The 26S proteasome is a large multiprotein complex involved in the regulated degradation of ubiquitinated proteins in the cell. The 26S proteasome has been shown to control an increasing number of essential biochemical mechanisms of the cellular lifecycle including DNA synthesis, repair, transcription, translation, and cell signal transduction. Concurrently, it is increasingly seen that malfunction of the ubiquitin proteasome system contributes to the pathogenesis of disease. The recent identification of four molecular chaperones, in addition to five previously identified chaperones, have provided mechanistic insight into how this cellular megastructure is assembled in the cell. These data, together with new insights into the structure and function of the proteasome, provide a much better understanding of this complex protease.
Essays in Biochemistry | 2005
Robert Layfield; James Lowe; Lynn Bedford
As in all other mammalian tissues, the UPS (ubiquitin-proteasome system) is fundamental to normal brain function. A consistent feature of the major human neurodegenerative disorders is the accumulation of disease-related proteins, in non-native conformations, as protein aggregates within neurons or glial cells. Often the proteins in these aggregates are post-translationally conjugated with ubiquitin, suggesting a possible link between pathological protein-aggregation events in the nervous system and dysfunction of the UPS. Genetic evidence clearly demonstrates that disruption of ubiquitin-mediated processes can lead to neurodegeneration; however, the relationship between the UPS and idiopathic neurodegenerative disorders is less clear. In the latter cases, although a number of different mechanisms could potentially contribute to dysfunction of the UPS and promote the neurodegenerative process, whether UPS dysfunction is causally related to disease pathogenesis, or alternatively arises as a result of the pathological state, and indeed whether ubiquitinated inclusions are harmful or beneficial to cells, remains to be clarified.
Journal of Biological Chemistry | 2014
Shun Kageyama; Yu-shin Sou; Takefumi Uemura; Satoshi Kametaka; Tetsuya Saito; Ryosuke Ishimura; Tsuguka Kouno; Lynn Bedford; R. John Mayer; Myung-Shik Lee; Masayuki Yamamoto; Satoshi Waguri; Keiji Tanaka; Masaaki Komatsu
Background: Malfunctions in the ubiquitin-proteasome system cause accumulation of non-functional, potentially toxic protein aggregates. Results: The protein aggregates activate Nrf2 and are then excluded by autophagy in vivo. Conclusion: Both Nrf2 and autophagy serve as in vivo cellular adaptations to impaired proteasome. Significance: Cells contain networks of cellular defense mechanisms against defective proteostasis. The ubiquitin-proteasome system and autophagy are crucially important for proteostasis in cells. These pathways are interdependent, and dysfunction in either pathway causes accumulation of ubiquitin-positive aggregates, a hallmark of human pathological conditions. To elucidate in vivo compensatory action(s) against proteasomal dysfunction, we developed mice with reduced proteasome activity in their livers. The mutant mice exhibited severe liver damage, accompanied by formation of aggregates positive for ubiquitin and p62/Sqstm1, an adaptor protein for both selective autophagy and the anti-oxidative Keap1-Nrf2 pathway. These aggregates were selectively entrapped by autophagosomes, and pathological features of livers with impaired proteasome activity were exacerbated by simultaneous suppression of autophagy. In contrast, concomitant loss of p62/Sqstm1 had no apparent effect on the liver pathology though p62/Sqstm1 was indispensable for the aggregates formation. Furthermore, defective proteasome function led to transcriptional activation of the Nrf2, which served as a physiological adaptation. Our in vivo data suggest that cells contain networks of cellular defense mechanisms against defective proteostasis.
Journal of Alzheimer's Disease | 2011
Ritchie Williamson; Lidy van Aalten; David Mann; Bettina Platt; Florian Plattner; Lynn Bedford; John E. Mayer; David R. Howlett; Alessia Usardi; Calum Sutherland; Adam R. Cole
Collapsin response mediator protein 2 (CRMP2) is an abundant brain-enriched protein that regulates neurite outgrowth. It is phosphorylated by Cdk5 and GSK3, and these modifications are abnormally high in the brains of Alzheimers disease (AD) patients. Increased phosphorylation of CRMP2 is also apparent in mouse models of AD that express mutated AβPP and PSEN1, but not AβPP or tau alone, where it is detectable before the appearance of amyloid plaques and neurofibrillary tangles, suggesting it is an early event in AD pathogenesis. Here, we have extended these observations by showing that CRMP2 is not hyperphosphorylated in mice overexpressing mutated PSEN1 alone, or in cultured neurons treated with soluble, oligomeric Aβ42 peptide. Similarly, CRMP2 phosphorylation was not increased in a mouse model of severe neurodegeneration (PMSC-1 knockout) or in cultured neurons subjected to neurotoxic concentrations of NMDA or staurosporine. Most interestingly, CRMP2 phosphorylation was not increased in frontal cortex from patients with frontotemporal lobar degeneration associated with mutations in MAPT or with Pick bodies. Together, these observations are consistent with the hypothesis that abnormal phosphorylation of CRMP2 is specific to AD and occurs downstream of excessive processing of AβPP, but that neither excessive Aβ42 peptide nor neurotoxicity alone are sufficient to promote hyperphosphorylation.
Neuropathology and Applied Neurobiology | 2010
Natasha K Rogers; Simon Paine; Lynn Bedford; Robert Layfield
N. Rogers, S. Paine, L. Bedford and R. Layfield (2010) Neuropathology and Applied Neurobiology36, 113–124 The ubiquitin‐proteasome system: contributions to cell death or survival in neurodegeneration
Biochimica et Biophysica Acta | 2008
Lynn Bedford; David Hay; Simon Paine; Nooshin Rezvani; Maureen Mee; James Lowe; R. John Mayer
Neuropathological investigations have identified major hallmarks of chronic neurodegenerative disease. These include protein aggregates called Lewy bodies in dementia with Lewy bodies and Parkinsons disease. Mutations in the alpha-synuclein gene have been found in familial disease and this has led to intense focused research in vitro and in transgenic animals to mimic and understand Parkinsons disease. A decade of transgenesis has lead to overexpression of wild type and mutated alpha-synuclein, but without faithful reproduction of human neuropathology and movement disorder. In particular, widespread regional neuronal cell death in the substantia nigra associated with human disease has not been described. The intraneuronal protein aggregates (inclusions) in all of the human chronic neurodegenerative diseases contain ubiquitylated proteins. There could be several reasons for the accumulation of ubiquitylated proteins, including malfunction of the ubiquitin proteasome system (UPS). This hypothesis has been genetically tested in mice by conditional deletion of a proteasomal regulatory ATPase gene. The consequences of gene ablation in the forebrain include extensive neuronal death and the production of Lewy-like bodies containing ubiquitylated proteins as in dementia with Lewy bodies. Gene deletion in catecholaminergic neurons, including in the substantia nigra, recapitulates the neuropathology of Parkinsons disease.
Neuroscience Letters | 2009
Simon Paine; Lynn Bedford; Julian R. Thorpe; R. John Mayer; James R. Cavey; Nin Bajaj; Paul W. Sheppard; James Lowe; Robert Layfield
The major human neurodegenerative diseases are characterised by ubiquitin-positive intraneuronal inclusions, however the precise nature of the ubiquitin modifications in these structures is unclear. Using a monoclonal antibody specific for Lys63-linked polyubiquitin we have performed the first immunohistochemical analysis of linkage-specific ubiquitination in vivo associated with neurodegeneration. Immunoreactivity was detected within the pathological lesions of Alzheimers, Huntingtons and Parkinsons disease brains, although staining of Lewy bodies in the substantia nigra in Parkinsons disease was rare, indicating a selective involvement of Lys63-linked polyubiquitin in inclusion biogenesis in this disorder. Immunoreactivity was also a feature in neurons of proteasome-depleted mice, suggesting a proteasomal contribution to the degradation of Lys63-linked polyubiquitinated proteins in vivo.
Neuroscience Letters | 2011
Lynn Bedford; Robert Layfield; R. John Mayer; Junmin Peng; Ping Xu
A generality has been that polyubiquitin chain linkage can differentially address proteins for various physiological processes. 26S proteasomal degradation is the most established function of ubiquitin signalling, classically linked to Lys48 polyubiquitin chains. The other well-characterised polyubiquitin linkage, via Lys63, mediates nonproteolytic functions. However, there are five other lysine residues and ubiquitins amino terminus which can participate in polyubiquitination. Our 26S proteasome knockout mouse provides a unique opportunity to comprehensively investigate the ubiquitin signals in their physiological context in neurones following genetic inhibition of the proteasome, using quantitative mass spectrometry of ubiquitin linkage-specific signature peptides. We provide the first evidence for diverse polyubiquitin chains in mammalian neurones in vivo and show that polyubiquitin linked via Lys6, Lys11, Lys29 and Lys48, but not Lys63, accumulates upon 26S proteasome dysfunction. This adaptable nature of ubiquitin signals for proteasomal targeting could reflect the extensive cellular processes which are regulated by proteasome proteolysis and/or may involve specific ubiquitin linkage preferences for subsets of proteins in mammalian neurones. Our molecular pathological findings make a significant contribution to the understanding of ubiquitin signalling in ubiquitin-proteasome function.