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J. Douglas Mitchell

Bio: J. Douglas Mitchell is an academic researcher from University of Central Lancashire. The author has contributed to research in topics: Motor neurone disease & Transthyretin. The author has an hindex of 4, co-authored 4 publications receiving 2385 citations.

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
TL;DR: The results from the ALSAQ-40 and EQ-5D descriptive system indicate that patients' HRQL decreases systematically with increasing severity of disease.

83 citations

Journal ArticleDOI
TL;DR: Possible changes in brain metabolites in motor neurone disease/amytrophic lateral sclerosis (MND/ALS) were investigated using 1H magnetic resonance spectroscopy and it could form a useful method for monitoring the effects of future trial treatment regimens.

63 citations

Journal ArticleDOI
TL;DR: Qualitative findings revealed a number of barriers delaying the uptake of social services homecare in MND/ALS, including limited understanding of the disease amongst service providers and lack of awareness of service entitlement amongst patients and carers.
Abstract: Many patients with the terminal condition motor neurone disease/amyotrophic lateral sclerosis (MND/ALS) do not access social service homecare, which may have implications for the location of end-of-life care. We aimed to identify factors related to uptake of such care in MND/ALS. A case note review of patients at a UK MND/ALS clinic (N = 97) provided data concerning disease onset and severity, demographic variables and care received. Narrative interviews with people with MND/ALS (N = 24) and family carers (N = 18) explored their perspectives on social services homecare.Quantitative analyses highlighted the role of increasing disease severity and age for social services homecare uptake. However, qualitative findings revealed a number of barriers delaying the uptake of such care. ‘Internal’ issues focused on retaining control and normality within the home. ‘External’ issues arose from limited understanding of the disease amongst service providers and lack of awareness of service entitlement amongst patients...

41 citations

Journal ArticleDOI
TL;DR: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and debilitative disease with a historically poor prognosis as mentioned in this paper .

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 Gibbs1, J. Raphael Gibbs6, 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. Scholz1, Sonja W. Scholz10, Jamie Duckworth1, Jinhui Ding1, Daniel W. Harmer11, Dena G. Hernandez6, Dena G. Hernandez1, Janel O. Johnson1, Janel O. Johnson6, 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. Rothstein9, 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. Traynor9, 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
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

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
24 Sep 2015-Cell
TL;DR: It is demonstrated that the disease-related RBP hnRNPA1 undergoes liquid-liquid phase separation (LLPS) into protein-rich droplets mediated by a low complexity sequence domain (LCD), and suggested that LCD-mediated LLPS contributes to the assembly of stress granules and their liquid properties.

1,947 citations