Author
J. de Belleroche
Other affiliations: UCL Institute of Neurology
Bio: J. de Belleroche is an academic researcher from Imperial College London. The author has contributed to research in topics: Amyotrophic lateral sclerosis & Striatum. The author has an hindex of 25, co-authored 52 publications receiving 2437 citations. Previous affiliations of J. de Belleroche include UCL Institute of Neurology.
Papers published on a yearly basis
Papers
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TL;DR: A locus on chromosome 9p21.3-p13.3 is linked to ALS-FTD in a four-generation, 50-member Scandinavian family affected with ALS and frontotemporal dementia.
Abstract: OBJECTIVE: To perform genetic linkage analysis in a family affected with ALS and frontotemporal dementia (FTD). METHODS: The authors performed a genome-wide linkage analysis of a four-generation, 5 ...
363 citations
King's College London1, University of Milan2, University of Massachusetts Medical School3, Imperial College London4, Trinity College, Dublin5, Emory University6, Hospital General Universitario Gregorio Marañón7, University Medical Center Utrecht8, University of Padua9, University Hospitals Birmingham NHS Foundation Trust10, Australian School of Advanced Medicine11, Montreal Neurological Institute and Hospital12, University of Birmingham13, University of Sheffield14, University of Oxford15, Worcester Polytechnic Institute16
TL;DR: In this paper, an exome-wide rare variant burden analysis of 363 index cases with familial ALS (FALS) was performed and the results revealed an excess of patient variants within TUBA4A, the gene encoding the Tubulin, Alpha 4A protein.
268 citations
TL;DR: Changes were observed in gene sets associated with synaptic vesicle recycling, transmitter release and cytoskeletal dynamics that suggest multiple, small but synergistic changes in gene expression that affect nerve terminal function.
Abstract: Schizophrenia is a severe psychiatric disorder with a world-wide prevalence of 1%. The pathophysiology of the illness is not understood, but is thought to have a strong genetic component with some environmental influences on aetiology. To gain further insight into disease mechanism, we used microarray technology to determine the expression of over 30 000 mRNA transcripts in post-mortem tissue from a brain region associated with the pathophysiology of the disease (Brodmann area 10: anterior prefrontal cortex) in 28 schizophrenic and 23 control patients. We then compared our study (Charing Cross Hospital prospective collection) with that of an independent prefrontal cortex dataset from the Harvard Brain Bank. We report the first direct comparison between two independent studies. A total of 51 gene expression changes have been identified that are common between the schizophrenia cohorts, and 49 show the same direction of disease-associated regulation. In particular, changes were observed in gene sets associated with synaptic vesicle recycling, transmitter release and cytoskeletal dynamics. This strongly suggests multiple, small but synergistic changes in gene expression that affect nerve terminal function.
187 citations
TL;DR: Two compartments of striatal synaptosome dopamine were identified by differential labelling with the isotopic presursors, L-tyrosine and Dopa, and from specific radioactivity measurement, showing that presynaptic cholinergic receptors were operational, excitatory nicotinic receptors in the former case and inhibitory muscarinic in the latter.
167 citations
TL;DR: Electron microscopy of the vesicle suspension showed that vesicles were by far the most abundant morphological entities, and the amino acid content of the purified vesicular fraction was examined and the two amino acids appearing in the most significant amounts were found to be taurine and glutamate.
Abstract: Synaptic vesicles were prepared from rat cerebral cortex and separated by gel filtration from small molecular weight compounds contaminating this fraction. Electron microscopy of the vesicle suspension showed that vesicles were by far the most abundant morphological entities. The amino acid content of the purified vesicle fraction was examined and the two amino acids appearing in the most significant amounts were found to be taurine and glutamate. This amino acid pool was not osmotically sensitive as is the vesicular pool of ACh and remained attached to the vesicular protein after passage through Sephadex columns equilibrated in water. However, amino acids added to the vesicle fraction prior to passage through Sephadex did not become associated with this pool and this indicated that the vesicular pool was not likely to be an artifact due to the vesicular protein non-specifically adsorbing amino acids. The release of taurine from incubated synaptosome beds was studied and elevated medium K+ (56 mm) was found to cause a small increase (36 per cent) in the amount of the taurine released to the medium. During the same experiments another physiologically active amino acid, glutamate, was released in more significant amounts, increasing in the medium by 186 per cent. The possible significance of the presence of taurine is discussed.
135 citations
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TL;DR: It is found that repeat expansion in C9ORF72 is a major cause of both FTD and ALS, suggesting multiple disease mechanisms.
4,153 citations
National Institutes of Health1, Cardiff University2, Erasmus University Rotterdam3, VU University Amsterdam4, University of Manchester5, University College London6, University of Helsinki7, University of Oulu8, Johns Hopkins University9, Georgetown University10, Illumina11, University Hospital of Wales12, University of Eastern Finland13, University of Miami14, University of Turin15, University of Cagliari16, The Catholic University of America17, Microsoft18, University of Toronto19, University of Würzburg20, University of Washington21, Aneurin Bevan University Health Board22
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
2,465 citations
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
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