Selina Wray

University College London, Londinium, England, United Kingdom

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Publications (24)167.56 Total impact

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    ABSTRACT: The alternative splicing of the tau gene, MAPT, generates six protein isoforms in the adult human CNS. Tau splicing is developmentally regulated and dysregulated in disease. Mutations in MAPT that alter tau splicing cause frontotemporal dementia (FTD) with tau pathology, providing evidence for a causal link between altered tau splicing and disease. The use of induced pluripotent stem cell (iPSC) derived neurons has revolutionized the way we model neurological disease in vitro. However, as most tau mutations are located within or around the alternatively spliced exon 10, it is important that iPSC-neurons splice tau appropriately in order to be used as disease models. To address this issue, we analysed the expression, and splicing of tau in iPSC-derived cortical neurons from control patients and FTD patients with the 10+16 intronic mutation in MAPT. We show that control neurons only express the fetal tau isoform (0N3R), even at extended time points of 100 days in vitro. Neurons from FTD patients with the 10+16 mutation in MAPT express both 0N3R and 0N4R tau isoforms, demonstrating that this mutation overrides the developmental regulation of exon 10 inclusion in our in vitro model. Further, at extended time-points of 365 days in vitro, we observe a switch in tau splicing to include six tau isoforms as seen the adult human CNS. Our results demonstrate the importance of neuronal maturity for use in in vitro modeling and provide a system that will be important for understanding the functional consequences of altered tau splicing. © The Author 2015. Published by Oxford University Press.
    Human Molecular Genetics 07/2015; DOI:10.1093/hmg/ddv246
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    ABSTRACT: The cerebellum forms a highly ordered and indispensible component of motor function within the adult neuraxis, consisting of several distinct cellular subtypes. Cerebellar disease, through a variety of genetic and acquired causes, results in the loss of function of defined subclasses of neurons, and remains a significant and untreatable healthcare burden. The scarcity of therapies in this arena can partially be explained by unresolved disease mechanisms due to inaccessibility of human cerebellar neurons in a relevant experimental context where initiating disease mechanisms could be functionally elucidated, or drug screens conducted. In this review we discuss the potential promise of human induced pluripotent stem cells (hiPSC; or induced pluripotent stem cells (iPSC) in the following) for regenerative neurology, with a particular emphasis on in vitro modelling of cerebellar degeneration. We discuss progress made thus far using human iPSC-based models of neurodegeneration, noting the relatively slower pace of discovery made in modelling cerebellar dysfunction. We conclude by speculating how strategies attempting cerebellar differentiation from human iPSCs can be refined to allow the generation of accurate disease models. This in turn will allow deeper mechanistic dissection of cerebellar pathophysiology to inform mechanistically rationalised therapies, which are desperately needed in this arena.
    Journal of neurogenetics 05/2015; DOI:10.3109/01677063.2015.1053478
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    ABSTRACT: Neurodegeneration with brain iron accumulation (NBIA) is a group of disorders characterised by dystonia, parkinsonism and spasticity. Iron accumulates in the basal ganglia and may be accompanied by Lewy bodies, axonal swellings and hyperphosphorylated tau depending on NBIA subtype. Mutations in 10 genes have been associated with NBIA that include Ceruloplasmin (Cp) and Ferritin Light Chain (FTL), both directly involved in iron homeostasis, as well as Pantothenate Kinase 2 (PANK2), Phospholipase A2 group 6 (PLA2G6), Fatty acid hydroxylase 2 (FA2H), Coenzyme A synthase (COASY), C19orf12, WDR45 and DCAF17 (C2orf37). These genes are involved in seemingly unrelated cellular pathways, such as lipid metabolism, Coenzyme A synthesis and autophagy. A greater understanding of the cellular pathways that link these genes and the disease mechanisms leading to iron dyshomeostasis is needed. Additionally, the major overlap seen between NBIA and more common neurodegenerative diseases may highlight conserved disease processes. In this review, we will discuss clinical and pathological findings for each NBIA-related gene, discuss proposed disease mechanisms such as mitochondrial health, oxidative damage, autophagy/mitophagy and iron homeostasis and speculate potential overlap between NBIA subtypes. This article is protected by copyright. All rights reserved.
    Neuropathology and Applied Neurobiology 04/2015; DOI:10.1111/nan.12242
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    ABSTRACT: C9orf72 hexanucleotide repeat expansions are the most common cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) worldwide. The clinical presentation is often indistinguishable from classic FTD or ALS, although neuropsychiatric symptoms are more prevalent and, for ALS, behavioural and cognitive symptoms occur more frequently. Pathogenic repeat length is in the hundreds or thousands, but the minimum length that increases risk of disease, and how or whether the repeat size affects phenotype, are unclear. Like in many patients with FTD and ALS, neuronal inclusions that contain TARDBP are seen, but are not universal, and the characteristic pathological finding is of dipeptide repeat (DPR) proteins, formed by unconventional repeat-associated non-ATG translation. Possible mechanisms of neurodegeneration include loss of C9orf72 protein and function, RNA toxicity, and toxicity from the DPR proteins, but which of these is the major pathogenic mechanism is not yet certain. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Lancet Neurology 01/2015; 14(3). DOI:10.1016/S1474-4422(14)70233-9
  • Biophysical Journal 01/2015; 108(2):611a. DOI:10.1016/j.bpj.2014.11.3324
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    ABSTRACT: An expanded hexanucleotide repeat in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Although 0-30 hexanucleotide repeats are present in the general population, expansions >500 repeats are associated with C9ALS/FTD. Large C9ALS/FTD expansions share a common haplotype and whether these expansions derive from a single founder or occur more frequently on a predisposing haplotype is yet to be determined and is relevant to disease pathomechanisms. Furthermore, although cases carrying 50-200 repeats have been described, their role and the pathogenic threshold of the expansions remain to be identified and carry importance for diagnostics and genetic counseling. We present clinical and genetic data from a UK ALS cohort and report the detailed molecular study of an atypical somatically unstable expansion of 90 repeats. Our results across different tissues provide evidence for the pathogenicity of this repeat number by showing they can somatically expand in the central nervous system to the well characterized pathogenic range. Our results support the occurrence of multiple expansion events for C9ALS/FTD.
    Neurobiology of Aging 08/2014; 36(1). DOI:10.1016/j.neurobiolaging.2014.07.037
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    ABSTRACT: Compelling evidence indicates that two autosomal recessive Parkinson's disease genes, PINK1 (PARK6) and Parkin (PARK2), cooperate to mediate the autophagic clearance of damaged mitochondria (mitophagy). Mutations in the F-box domain-containing protein Fbxo7 (encoded by PARK15) also cause early-onset autosomal recessive Parkinson's disease, by an unknown mechanism. Here we show that Fbxo7 participates in mitochondrial maintenance through direct interaction with PINK1 and Parkin and acts in Parkin-mediated mitophagy. Cells with reduced Fbxo7 expression showed deficiencies in translocation of Parkin to mitochondria, ubiquitination of mitofusin 1 and mitophagy. In Drosophila, ectopic overexpression of Fbxo7 rescued loss of Parkin, supporting a functional relationship between the two proteins. Parkinson's disease-causing mutations in Fbxo7 interfered with this process, emphasizing the importance of mitochondrial dysfunction in Parkinson's disease pathogenesis.
    Nature Neuroscience 08/2013; 16(9). DOI:10.1038/nn.3489
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    ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by pathological deposits of β-amyloid (Aβ) in senile plaques, intracellular neurofibrillary tangles (NFTs) comprising hyperphosphorylated aggregated tau, synaptic dysfunction and neuronal death. Substantial evidence indicates that disrupted neuronal calcium homeostasis is an early event in AD that could mediate synaptic dysfunction and neuronal toxicity. Sodium calcium exchangers (NCXs) play important roles in regulating intracellular calcium and accumulating data suggests that reduced NCX function, following aberrant proteolytic cleavage of these exchangers, may contribute to neurodegeneration. Here we show that elevated calpain, but not caspase-3, activity is a prominent feature of AD brain. In addition, we observe increased calpain-mediated cleavage of NCX3, but not a related family member NCX1, in AD brain relative to unaffected tissue and that from other neurodegenerative conditions. Moreover, the extent of NCX3 proteolysis correlated significantly with amounts of Aβ1-42. We also show that exposure of primary cortical neurons to oligomeric Aβ1-42 results in calpain-dependent cleavage of NCX3 and we demonstrate that loss of NCX3 function is associated with Aβ toxicity. Our findings suggest that Aβ mediates calpain cleavage of NCX3 in AD brain, and therefore that reduced NCX3 activity could contribute to the sustained increases in intraneuronal calcium concentrations that are associated with synaptic and neuronal dysfunction in AD. This article is protected by copyright. All rights reserved.
    Aging cell 08/2013; 13(1). DOI:10.1111/acel.12148
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    ABSTRACT: Valosin-containing protein (VCP) is a highly expressed member of the type II AAA+ ATPase family. VCP mutations are the cause of inclusion body myopathy, Paget's disease of the bone, and frontotemporal dementia (IBMPFD) and they account for 1%-2% of familial amyotrophic lateral sclerosis (ALS). Using fibroblasts from patients carrying three independent pathogenic mutations in the VCP gene, we show that VCP deficiency causes profound mitochondrial uncoupling leading to decreased mitochondrial membrane potential and increased mitochondrial oxygen consumption. This mitochondrial uncoupling results in a significant reduction of cellular ATP production. Decreased ATP levels in VCP-deficient cells lower their energy capacity, making them more vulnerable to high energy-demanding processes such as ischemia. Our findings propose a mechanism by which pathogenic VCP mutations lead to cell death.
    Neuron 03/2013; 78(1). DOI:10.1016/j.neuron.2013.02.028
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    ABSTRACT: Our understanding of the molecular mechanisms of many neurological disorders has been greatly enhanced by the discovery of mutations in genes linked to familial forms of these diseases. These have facilitated the generation of cell and animal models that can be used to understand the underlying molecular pathology. Recently, there has been a surge of interest in the use of patient-derived cells, due to the development of induced pluripotent stem cells and their subsequent differentiation into neurons and glia. Access to patient cell lines carrying the relevant mutations is a limiting factor for many centres wishing to pursue this research. We have therefore generated an open-access collection of fibroblast lines from patients carrying mutations linked to neurological disease. These cell lines have been deposited in the National Institute for Neurological Disorders and Stroke (NINDS) Repository at the Coriell Institute for Medical Research and can be requested by any research group for use in in vitro disease modelling. There are currently 71 mutation-defined cell lines available for request from a wide range of neurological disorders and this collection will be continually expanded. This represents a significant resource that will advance the use of patient cells as disease models by the scientific community.
    PLoS ONE 08/2012; 7(8). DOI:10.1371/journal.pone.0043099
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    ABSTRACT: BACKGROUND: TRPV4 mutations have been identified in Charcot-Marie-Tooth type 2 (CMT2), scapuloperoneal spinal muscular atrophy and distal hereditary motor neuropathy (dHMN). OBJECTIVE: We aimed to screen the TRPV4 gene in 422 British patients with inherited neuropathy for potentially pathogenic mutations. METHODS: We sequenced TRPV4 coding regions and splice junctions in 271 patients with CMT2 and 151 patients with dHMN. Mutations were clinically and genetically characterised and screened in ≥345 matched controls. RESULTS: 13 missense and nonsense variants were identified, of which five were novel and absent from controls (G20R, E218K, N302Y, Y567X and T701I). N302Y and T701I mutations were present in typical CMT2 cases and are potentially pathogenic based on in silico analyses. G20R was detected in a patient with dHMN and her asymptomatic father and is possibly pathogenic with variable expressivity. The Y567X variant segregated with disease in a family with severe CMT2 but also with a MFN2 mutation reported to cause a mild CMT2 phenotype. Although Y567X caused nonsense mediated mRNA decay, the amount of TRPV4 protein on western blotting of patient lymphoblasts was no different to control. Y567X is therefore unlikely to be pathogenic. E218K is unlikely to be pathogenic based on segregation. CONCLUSIONS: In this comprehensive analysis of the TRPV4 gene, we identified mutations in <1% of patients with CMT2/dHMN. We found that TRPV4 likely harbours many missense and nonsense non-pathogenic variants that should be analysed in detail to prove pathogenicity before results are given to patients.
    Journal of neurology, neurosurgery, and psychiatry 07/2012; 83(12). DOI:10.1136/jnnp-2012-303055
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    ABSTRACT: The MAPT (microtubule-associated protein tau) locus is one of the most remarkable in neurogenetics due not only to its involvement in multiple neurodegenerative disorders, including progressive supranuclear palsy, corticobasal degeneration, Parksinson's disease and possibly Alzheimer's disease, but also due its genetic evolution and complex alternative splicing features which are, to some extent, linked and so all the more intriguing. Therefore, obtaining robust information regarding the expression, splicing and genetic regulation of this gene within the human brain is of immense importance. In this study, we used 2011 brain samples originating from 439 individuals to provide the most reliable and coherent information on the regional expression, splicing and regulation of MAPT available to date. We found significant regional variation in mRNA expression and splicing of MAPT within the human brain. Furthermore, at the gene level, the regional distribution of mRNA expression and total tau protein expression levels were largely in agreement, appearing to be highly correlated. Finally and most importantly, we show that while the reported H1/H2 association with gene level expression is likely to be due to a technical artefact, this polymorphism is associated with the expression of exon 3-containing isoforms in human brain. These findings would suggest that contrary to the prevailing view, genetic risk factors for neurodegenerative diseases at the MAPT locus are likely to operate by changing mRNA splicing in different brain regions, as opposed to the overall expression of the MAPT gene.
    Human Molecular Genetics 06/2012; 21(18):4094-103. DOI:10.1093/hmg/dds238
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    ABSTRACT: Alzheimer's disease (AD) is the most common neurodegenerative disease and it poses an ever-increasing burden to an aging population. Several loci responsible for the rare, autosomal dominant form of AD have been identified (APP, PS1 and PS2), and these have facilitated the development of the amyloid cascade hypothesis of AD aetiology. The late onset form of the disease (LOAD) is poorly defined genetically, and up until recently the only known risk factor was the ε4 allele of APOE. Recent genome-wide association studies (GWAS) have identified common genetic variants that increase risk of LOAD. Two of the genes highlighted in these studies, CLU and CR1, suggest a role for the complement system in the aetiology of AD. In this review we analyse the evidence for an involvement of complement in AD. In particular we focus on one gene, CR1, and its role in the complement cascade. CR1 is a receptor for the complement fragments C3b and C4b and is expressed on many different cell types, particularly in the circulatory system. We look at the evidence for genetic polymorphisms in the gene and the possible physiological effects of these well-documented changes. Finally, we discuss the possible impact of CR1 genetic polymorphisms in relation to the amyloid cascade hypothesis of AD and the way in which CR1 may lead to AD pathogenesis.
    Immunobiology 07/2011; 217(2):244-50. DOI:10.1016/j.imbio.2011.07.017
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    ABSTRACT: A number of recent studies have described cases with tau-positive globular oligodendroglial inclusions (GOIs) and such cases have overlapping pathological features with progressive supranuclear palsy (PSP), but present with clinical features of motor neuron disease (MND) and/or frontotemporal dementia (FTD). These two clinical phenotypes have been published independently and as a result, have come to be considered as distinct disease entities. We describe the clinicopathological and biochemical features of two cases with GOIs: one with clinical symptoms suggestive of MND and the other with FTD. Histological changes in our two cases were consistent with their clinical symptoms; the MND case had severe neurodegeneration in the primary motor cortex and corticospinal tract, whereas the FTD case had severe involvement of the frontotemporal cortices and associated white matter. Immunohistochemistry in both cases revealed significant 4-repeat (4R) tau pathology primarily in the form of GOIs, but also in astrocytes and neurons. Astrocytic tau pathology was morphologically similar to that seen in PSP, but in contrast was consistently negative for Gallyas silver staining. Tau-specific western blotting revealed 68, 64 and 35 kDa bands, showing further overlap with PSP. The underlying neuropathological features of these two cases were similar, with the major difference relating to the regional distribution of pathology and resulting clinical symptoms and signs. The globular nature of glial inclusions and the non-fibrillar properties of tau in astrocytes are characteristic features that allow them to be distinguished from PSP and other tauopathies. We, therefore, propose the term globular glial tauopathy as an encompassing term to classify this emerging class of 4R tauopathy.
    Acta Neuropathologica 07/2011; 122(4):415-28. DOI:10.1007/s00401-011-0857-4
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    Selina Wray, Patrick A Lewis
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    ABSTRACT: Parkinson's disease (PD) represents a major challenge for health care systems around the world: it is the most common degenerative movement disorder of old age, affecting over 100,000 people in the UK alone (Schrag et al., 2000). Despite the remarkable success of treatments directed at potentiating or replacing dopamine within the brain, which can relieve symptoms for over a decade, PD remains an incurable and invariably fatal disorder. As such, efforts to understand the processes that lead to cell death in the brains of patients with PD are a priority for neurodegenerative researchers. A great deal of progress has been made in this regard by taking advantage of advances in genetics, initially by the identification of genes responsible for rare Mendelian forms of PD (outlined in Table 1), and more recently by applying genome wide association studies (GWAS) to the sporadic form of the disease (Hardy et al., 2009). Several such GWAS have now been carried out, with a meta-analysis currently under way. Using over 6000 cases and 10,000 controls, two of these studies have identified variation at a number of loci as being associated with an increased risk of disease (Satake et al., 2009; Simon-Sanchez et al., 2009). Three genes stand out as candidates from these studies - the SNCA gene, coding for α-synuclein, the LRRK2 gene, coding for leucine rich repeat kinase 2, and MAPT, coding for the microtubule-associated protein tau. Mutations at all three of these loci have been associated with Mendelian forms of disease presenting with the clinical syndrome of Parkinsonism, however only SNCA and LRRK2 have been previously associated with pathologically defined PD (Hardy et al., 2009). Point mutations in α-synuclein, along with gene multiplication events, result in autosomal dominant PD, often with a significant dementia component. In addition to this, α-synuclein is the principle component of the main pathological hallmark of idiopathic PD, the Lewy body, making it an unsurprising hit in the GWAS (Spillantini et al., 1997). Mutations in LRRK2 are the most common genetic cause of PD, and so again made this gene a likely candidate as a susceptibility locus for the sporadic form of disease (Kumari and Tan, 2009). More surprising, perhaps, was the identification of tau as a susceptibility factor for Parkinson's. In this review we will outline the role of tau in neurodegeneration and in different forms of Parkinsonism, and speculate as to what the functional basis of the association between MAPT and PD might be.
    Frontiers in Psychiatry 12/2010; 1:150. DOI:10.3389/fpsyt.2010.00150
  • Diane P Hanger, Selina Wray
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    ABSTRACT: Deposition of highly phosphorylated tau in the brain is the most significant neuropathological and biochemical characteristic of the group of neurodegenerative disorders termed the tauopathies. The discovery of tau fragments in these diseases suggests that tau cleavage and tau phosphorylation, both of which induce conformational changes in tau, could each have roles in disease pathogenesis. The identities of the proteases responsible for degrading tau, resulting in the appearance of truncated tau species in physiological and pathological conditions, are not known. Several fragments of tau are reported to have pro-aggregation properties, but the lack of disease-relevant cell models of tau aggregation has hampered investigation of the effects of tau aggregation on normal cellular functioning. In the present paper, we describe our findings of N-terminally truncated tau in the brain in a subgroup of the tauopathies in which tau isoforms containing four microtubule-binding domains predominate. We also discuss the evidence for the involvement of proteases in the generation of tau pathology in neurodegenerative disease, since these enzymes warrant further investigation as potential therapeutic targets in the tauopathies.
    Biochemical Society Transactions 08/2010; 38(4):1016-20. DOI:10.1042/BST0381016
  • Alzheimer's and Dementia 07/2010; 6(4). DOI:10.1016/j.jalz.2010.05.660
  • Selina Wray, Wendy Noble
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 09/2009; 29(31):9665-7. DOI:10.1523/JNEUROSCI.2234-09.2009
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    ABSTRACT: The microtubule-associated protein tau can associate with various other proteins in addition to tubulin, including the SH3 domains of Src family tyrosine kinases. Tau is well known to aggregate to form hyperphosphorylated filamentous deposits in several neurodegenerative diseases (tauopathies) including Alzheimer disease. We now report that tau can bind to SH3 domains derived from the p85alpha subunit of phosphatidylinositol 3-kinase, phospholipase Cgamma1, and the N-terminal (but not the C-terminal) SH3 of Grb2 as well as to the kinases Fyn, cSrc, and Fgr. However, the short inserts found in neuron-specific isoforms of Src prevented the binding of tau. The experimentally determined binding of tau peptides is well accounted for when modeled into the peptide binding cleft in the SH3 domain of Fyn. After phosphorylation in vitro or in transfected cells, tau showed reduced binding to SH3 domains; no binding was detected with hyperphosphorylated tau isolated from Alzheimer brain, but SH3 binding was restored by phosphatase treatment. Tau mutants with serines and threonines replaced by glutamate, to mimic phosphorylation, showed reduced SH3 binding. These results strongly suggest that tau has a potential role in cell signaling in addition to its accepted role in cytoskeletal assembly, with regulation by phosphorylation that may be disrupted in the tauopathies including Alzheimer disease.
    Journal of Biological Chemistry 07/2008; 283(26):18177-86. DOI:10.1074/jbc.M709715200

Publication Stats

470 Citations
167.56 Total Impact Points

Institutions

  • 2014
    • University College London
      • Department of Molecular Neuroscience
      Londinium, England, United Kingdom
  • 2010–2013
    • UCL Eastman Dental Institute
      Londinium, England, United Kingdom
  • 2006–2013
    • King's College London
      • • Institute of Psychiatry
      • • MRC Centre for Neurodegeneration Research
      Londinium, England, United Kingdom