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Emanuele Buratti

Bio: Emanuele Buratti is an academic researcher from International Centre for Genetic Engineering and Biotechnology. The author has contributed to research in topics: RNA splicing & Exon. The author has an hindex of 62, co-authored 207 publications receiving 16895 citations. Previous affiliations of Emanuele Buratti include AREA Science Park & French Institute of Health and Medical Research.


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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 aim of this study was to identify the phosphorylation sites and responsible kinases, and to clarify the pathological significance ofosphorylation of TDP‐43.
Abstract: Objective TAR DNA-binding protein of 43kDa (TDP-43) is deposited as cytoplasmic and intranuclear inclusions in brains of patients with frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). Previous studies reported that abnormal phosphorylation takes place in deposited TDP-43. The aim of this study was to identify the phosphorylation sites and responsible kinases, and to clarify the pathological significance of phosphorylation of TDP-43. Methods We generated multiple antibodies specific to phosphorylated TDP-43 by immunizing phosphopeptides of TDP-43, and analyzed FTLD-U and ALS brains by immunohistochemistry, immunoelectron microscopy, and immunoblots. In addition, we performed investigations aimed at identifying the responsible kinases, and we assessed the effects of phosphorylation on TDP-43 oligomerization and fibrillization. Results We identified multiple phosphorylation sites in carboxyl-terminal regions of deposited TDP-43. Phosphorylation-specific antibodies stained more inclusions than antibodies to ubiquitin and, unlike existing commercially available anti–TDP-43 antibodies, did not stain normal nuclei. Ultrastructurally, these antibodies labeled abnormal fibers of 15nm diameter and on immunoblots recognized hyperphosphorylated TDP-43 at 45kDa, with additional 18 to 26kDa fragments in sarkosyl-insoluble fractions from FTLD-U and ALS brains. The phosphorylated epitopes were generated by casein kinase-1 and -2, and phosphorylation led to increased oligomerization and fibrillization of TDP-43. Interpretation These results suggest that phosphorylated TDP-43 is a major component of the inclusions, and that abnormal phosphorylation of TDP-43 is a critical step in the pathogenesis of FTLD-U and ALS. Phosphorylation-specific antibodies will be powerful tools for the investigation of these disorders. Ann Neurol 2008

622 citations

Journal ArticleDOI
TL;DR: TDP‐43, a nuclear protein not previously described to bind RNA, is identified as the factor binding specifically to the (TG)m sequence, providing a new therapeutic target to correct aberrant splicing of exon 9 in CF patients.
Abstract: Alternative splicing of human cystic fibrosis transmembrane conductance regulator (CFTR) exon 9 is regulated by a combination of cis-acting elements distributed through the exon and both flanking introns (IVS8 and IVS9). Several studies have identified in the IVS8 intron 3' splice site a regulatory element that is composed of a polymorphic (TG)m(T)n repeated sequence. At present, no cellular factors have been identified that recognize this element. We have identified TDP-43, a nuclear protein not previously described to bind RNA, as the factor binding specifically to the (TG)m sequence. Transient TDP-43 overexpression in Hep3B cells results in an increase in exon 9 skipping. This effect is more pronounced with concomitant overexpression of SR proteins. Antisense inhibition of endogenous TDP-43 expression results in increased inclusion of exon 9, providing a new therapeutic target to correct aberrant splicing of exon 9 in CF patients. The clinical and biological relevance of this finding in vivo is demonstrated by our characterization of a CF patient carrying a TG10T9(DeltaF508)/TG13T3(wt) genotype leading to a disease-causing high proportion of exon 9 skipping.

616 citations

Journal ArticleDOI
TL;DR: The results show that this protein contains two fully functional RNA recognition motif (RRM) domains with distinct RNA/DNA binding characteristics, and in particular, the highly conserved Phe residues in the first RRM region play a key role in nucleic acid recognition.

599 citations

Journal ArticleDOI
TL;DR: It is reported that the ectopic expression of a ≈25-kDa TDP-43 fragment corresponding to the C-terminal truncation product of caspase-cleaved T DP-43 leads to the formation of toxic, insoluble, and ubiquitin- and phospho-positive cytoplasmic inclusions within cells.
Abstract: Inclusions of TAR DNA-binding protein-43 (TDP-43), a nuclear protein that regulates transcription and RNA splicing, are the defining histopathological feature of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-Us) and sporadic and familial forms of amyotrophic lateral sclerosis (ALS). In ALS and FTLD-U, aggregated, ubiquitinated, and N-terminally truncated TDP-43 can be isolated from brain tissue rich in neuronal and glial cytoplasmic inclusions. The loss of TDP-43 function resulting from inappropriate cleavage, translocation from the nucleus, or its sequestration into inclusions could play important roles in neurodegeneration. However, it is not known whether TDP-43 fragments directly mediate toxicity and, more specifically, whether their abnormal aggregation is a cause or consequence of pathogenesis. We report that the ectopic expression of a ≈25-kDa TDP-43 fragment corresponding to the C-terminal truncation product of caspase-cleaved TDP-43 leads to the formation of toxic, insoluble, and ubiquitin- and phospho-positive cytoplasmic inclusions within cells. The 25-kDa C-terminal fragment is more prone to phosphorylation at S409/S410 than full-length TDP-43, but phosphorylation at these sites is not required for inclusion formation or toxicity. Although this fragment shows no biological activity, its exogenous expression neither inhibits the function nor causes the sequestration of full-length nuclear TDP-43, suggesting that the 25-kDa fragment can induce cell death through a toxic gain-of-function. Finally, by generating a conformation-dependent antibody that detects C-terminal fragments, we show that this toxic cleavage product is specific for pathologic inclusions in human TDP-43 proteinopathies.

545 citations


Cited by
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TL;DR: The reprogramming of gene expression during EMT, as well as non-transcriptional changes, are initiated and controlled by signalling pathways that respond to extracellular cues, and the convergence of signalling pathways is essential for EMT.
Abstract: The transdifferentiation of epithelial cells into motile mesenchymal cells, a process known as epithelial-mesenchymal transition (EMT), is integral in development, wound healing and stem cell behaviour, and contributes pathologically to fibrosis and cancer progression. This switch in cell differentiation and behaviour is mediated by key transcription factors, including SNAIL, zinc-finger E-box-binding (ZEB) and basic helix-loop-helix transcription factors, the functions of which are finely regulated at the transcriptional, translational and post-translational levels. The reprogramming of gene expression during EMT, as well as non-transcriptional changes, are initiated and controlled by signalling pathways that respond to extracellular cues. Among these, transforming growth factor-β (TGFβ) family signalling has a predominant role; however, the convergence of signalling pathways is essential for EMT.

6,036 citations

Journal ArticleDOI
06 Oct 2006-Science
TL;DR: It is shown that TDP-43 is the major disease protein in both frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis.
Abstract: Ubiquitin-positive, tau- and alpha-synuclein-negative inclusions are hallmarks of frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. Although the identity of the ubiquitinated protein specific to either disorder was unknown, we showed that TDP-43 is the major disease protein in both disorders. Pathologic TDP-43 was hyper-phosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected central nervous system regions, including hippocampus, neocortex, and spinal cord. TDP-43 represents the common pathologic substrate linking these neurodegenerative disorders.

5,440 citations

01 Aug 2000
TL;DR: Assessment of medical technology in the context of commercialization with Bioentrepreneur course, which addresses many issues unique to biomedical products.
Abstract: BIOE 402. Medical Technology Assessment. 2 or 3 hours. Bioentrepreneur course. Assessment of medical technology in the context of commercialization. Objectives, competition, market share, funding, pricing, manufacturing, growth, and intellectual property; many issues unique to biomedical products. Course Information: 2 undergraduate hours. 3 graduate hours. Prerequisite(s): Junior standing or above and consent of the instructor.

4,833 citations

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 Swieten3, John C. van Swieten4, 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. 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