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Caroline Vance

Bio: Caroline Vance is an academic researcher from King's College London. The author has contributed to research in topics: Amyotrophic lateral sclerosis & Neurodegeneration. The author has an hindex of 31, co-authored 56 publications receiving 9164 citations. Previous affiliations of Caroline Vance include Imperial College London & Medical Research Council.


Papers
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Journal ArticleDOI
21 Mar 2008-Science
TL;DR: The evidence suggests a pathophysiological link between TDP-43 and ALS, and neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases.
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder characterized pathologically by ubiquitinated TAR DNA binding protein (TDP-43) inclusions. The function of TDP-43 in the nervous system is uncertain, and a mechanistic role in neurodegeneration remains speculative. We identified neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases. TARDBPM337V segregated with disease within one kindred and a genome-wide scan confirmed that linkage was restricted to chromosome 1p36, which contains the TARDBP locus. Mutant forms of TDP-43 fragmented in vitro more readily than wild type and, in vivo, caused neural apoptosis and developmental delay in the chick embryo. Our evidence suggests a pathophysiological link between TDP-43 and ALS.

2,425 citations

Journal ArticleDOI
27 Feb 2009-Science
TL;DR: A missense mutation in the gene encoding fused in sarcoma (FUS) in a British kindred, linked to ALS6, is identified, which suggests that a common mechanism may underlie motor neuron degeneration.
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is familial in 10% of cases. We have identified a missense mutation in the gene encoding fused in sarcoma (FUS) in a British kindred, linked to ALS6. In a survey of 197 familial ALS index cases, we identified two further missense mutations in eight families. Postmortem analysis of three cases with FUS mutations showed FUS-immunoreactive cytoplasmic inclusions and predominantly lower motor neuron degeneration. Cellular expression studies revealed aberrant localization of mutant FUS protein. FUS is involved in the regulation of transcription and RNA splicing and transport, and it has functional homology to another ALS gene, TARDBP, which suggests that a common mechanism may underlie motor neuron degeneration.

2,373 citations

Journal ArticleDOI
Aude Nicolas1, Kevin P. Kenna2, Alan E. Renton3, Alan E. Renton1  +432 moreInstitutions (78)
21 Mar 2018-Neuron
TL;DR: Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia and Charcot-Marie-Tooth type 2.

444 citations

Journal ArticleDOI
TL;DR: The identification and functional analyses of two novel and one known mutation in TARDBP that are identified as a result of extensive mutation analyses in a cohort of 296 patients with variable neurodegenerative diseases associated with TDP-43 histopathology support TARD BP mutations as a cause of ALS.
Abstract: The TAR DNA-binding protein 43 (TDP-43) has been identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U), defining a novel class of neurodegenerative conditions: the TDP-43 proteinopathies. The first pathogenic mutations in the gene encoding TDP-43 (TARDBP) were recently reported in familial and sporadic ALS patients, supporting a direct role for TDP-43 in neurodegeneration. In this study, we report the identification and functional analyses of two novel and one known mutation in TARDBP that we identified as a result of extensive mutation analyses in a cohort of 296 patients with variable neurodegenerative diseases associated with TDP-43 histopathology. Three different heterozygous missense mutations in exon 6 of TARDBP (p.M337V, p.N345K, and p.I383V) were identified in the analysis of 92 familial ALS patients (3.3%), while no mutations were detected in 24 patients with sporadic ALS or 180 patients with other TDP-43-positive neurodegenerative diseases. The presence of p.M337V, p.N345K, and p.I383V was excluded in 825 controls and 652 additional sporadic ALS patients. All three mutations affect highly conserved amino acid residues in the C-terminal part of TDP-43 known to be involved in protein-protein interactions. Biochemical analysis of TDP-43 in ALS patient cell lines revealed a substantial increase in caspase cleaved fragments, including the approximately 25 kDa fragment, compared to control cell lines. Our findings support TARDBP mutations as a cause of ALS. Based on the specific C-terminal location of the mutations and the accumulation of a smaller C-terminal fragment, we speculate that TARDBP mutations may cause a toxic gain of function through novel protein interactions or intracellular accumulation of TDP-43 fragments leading to apoptosis.

435 citations

Journal ArticleDOI
TL;DR: It is demonstrated that the expression of 38× and 72× G4C2 repeats form intranuclear RNA foci that initiate apoptotic cell death in neuronal cell lines and zebrafish embryos and proposed that RNA toxicity and protein sequestration may disrupt RNA processing and contribute to neurodegeneration.

420 citations


Cited by
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Journal ArticleDOI
Alan E. Renton1, Elisa Majounie1, Adrian James Waite2, Javier Simón-Sánchez3, Javier Simón-Sánchez4, Sara Rollinson5, J. Raphael Gibbs6, J. Raphael Gibbs1, Jennifer C. Schymick1, Hannu Laaksovirta7, John C. van Swieten4, John C. van Swieten3, Liisa Myllykangas7, Hannu Kalimo7, Anders Paetau7, Yevgeniya Abramzon1, Anne M. Remes8, Alice Kaganovich1, Sonja W. Scholz9, Sonja W. Scholz10, Sonja W. Scholz1, Jamie Duckworth1, Jinhui Ding1, Daniel W. Harmer11, Dena G. Hernandez1, Dena G. Hernandez6, Janel O. Johnson6, Janel O. Johnson1, Kin Y. Mok6, Mina Ryten6, Danyah Trabzuni6, Rita Guerreiro6, Richard W. Orrell6, James Neal2, Alexandra Murray12, J. P. Pearson2, Iris E. Jansen3, David Sondervan3, Harro Seelaar4, Derek J. Blake2, Kate Young5, Nicola Halliwell5, Janis Bennion Callister5, Greg Toulson5, Anna Richardson5, Alexander Gerhard5, Julie S. Snowden5, David M. A. Mann5, David Neary5, Mike A. Nalls1, Terhi Peuralinna7, Lilja Jansson7, Veli-Matti Isoviita7, Anna-Lotta Kaivorinne8, Maarit Hölttä-Vuori7, Elina Ikonen7, Raimo Sulkava13, Michael Benatar14, Joanne Wuu14, Adriano Chiò15, Gabriella Restagno, Giuseppe Borghero16, Mario Sabatelli17, David Heckerman18, Ekaterina Rogaeva19, Lorne Zinman19, Jeffrey D. Rothstein10, Michael Sendtner20, Carsten Drepper20, Evan E. Eichler21, Can Alkan21, Ziedulla Abdullaev1, Svetlana Pack1, Amalia Dutra1, Evgenia Pak1, John Hardy6, Andrew B. Singleton1, Nigel Williams2, Peter Heutink3, Stuart Pickering-Brown5, Huw R. Morris2, Huw R. Morris12, Huw R. Morris22, Pentti J. Tienari7, Bryan J. Traynor10, Bryan J. Traynor1 
20 Oct 2011-Neuron
TL;DR: The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases, and a large hexanucleotide repeat expansion in the first intron of C9ORF72 is shown.

3,784 citations

Journal ArticleDOI
19 Mar 2010-Cell
TL;DR: There is evidence for a remarkable convergence in the mechanisms responsible for the sensing, transduction, and amplification of inflammatory processes that result in the production of neurotoxic mediators in neurodegenerative diseases.

2,838 citations

Journal ArticleDOI
21 Mar 2008-Science
TL;DR: The evidence suggests a pathophysiological link between TDP-43 and ALS, and neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases.
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder characterized pathologically by ubiquitinated TAR DNA binding protein (TDP-43) inclusions. The function of TDP-43 in the nervous system is uncertain, and a mechanistic role in neurodegeneration remains speculative. We identified neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases. TARDBPM337V segregated with disease within one kindred and a genome-wide scan confirmed that linkage was restricted to chromosome 1p36, which contains the TARDBP locus. Mutant forms of TDP-43 fragmented in vitro more readily than wild type and, in vivo, caused neural apoptosis and developmental delay in the chick embryo. Our evidence suggests a pathophysiological link between TDP-43 and ALS.

2,425 citations

Journal ArticleDOI
27 Feb 2009-Science
TL;DR: Neuronal cytoplasmic protein aggregation and defective RNA metabolism thus appear to be common pathogenic mechanisms involved in ALS and possibly in other neurodegenerative disorders.
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal degenerative motor neuron disorder Ten percent of cases are inherited; most involve unidentified genes We report here 13 mutations in the fused in sarcoma/translated in liposarcoma (FUS/TLS) gene on chromosome 16 that were specific for familial ALS The FUS/TLS protein binds to RNA, functions in diverse processes, and is normally located predominantly in the nucleus In contrast, the mutant forms of FUS/TLS accumulated in the cytoplasm of neurons, a pathology that is similar to that of the gene TAR DNA-binding protein 43 (TDP43), whose mutations also cause ALS Neuronal cytoplasmic protein aggregation and defective RNA metabolism thus appear to be common pathogenic mechanisms involved in ALS and possibly in other neurodegenerative disorders

2,387 citations