Isoform-specific antibodies reveal distinct subcellular localizations of C9orf72 in amyotrophic lateral sclerosis.
Shangxi Xiao,Laura MacNair,Philip McGoldrick,Paul M. McKeever,Jesse R. McLean,Ming Zhang,Julia Keith,Lorne Zinman,Ekaterina Rogaeva,Janice Robertson +9 more
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TLDR
A noncoding hexanucleotide repeat expansion in C9orf72 is the most common cause of amyotrophic lateral sclerosis and frontotemporal lobar degeneration, and it has been reported that the repeat expansion causes a downregulation of C 9orf72 transcripts, suggesting that haploinsufficiency may contribute to disease pathogenesis.Abstract:
Objective
A noncoding hexanucleotide repeat expansion in C9orf72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) It has been reported that the repeat expansion causes a downregulation of C9orf72 transcripts, suggesting that haploinsufficiency may contribute to disease pathogenesis Two protein isoforms are generated from three alternatively spliced transcripts of C9orf72; a long form (C9-L) and a short form (C9-S), and their function(s) are largely unknown owing to lack of specific antibodies
Methods
To investigate C9orf72 protein properties, we developed novel antibodies that recognize either C9-L or C9-S Multiple techniques, including Western blot, immunohistochemistry, and coimmunoprecipitation, were used to determine the expression levels and subcellular localizations of C9-L and C9-S
Results
Investigation of expression of C9-L and C9-S demonstrated distinct biochemical profiles, region-specific changes, and distinct subcellular localizations in ALS tissues In particular, C9-L antibody exhibited a diffuse cytoplasmic staining in neurons and labeled large speckles in cerebellar Purkinje cells In contrast, C9-S antibody gave very specific labeling of the nuclear membrane in healthy neurons, with apparent relocalization to the plasma membrane of diseased motor neurons in ALS Coimmunoprecipitation experiments revealed an interaction of the C9-isoforms with both Importin β1 and Ran-GTPase, components of the nuclear pore complex
Interpretation
Using these antibodies, we have shown that C9orf72 may be involved in nucleocytoplasmic shuttling and this may have relevance to pathophysiology of ALS/FTLD Our antibodies have provided improved detection of C9orf72 protein isoforms, which will help elucidate its physiological function and role in ALS/FTLD Ann Neurol 2015;78:568–583read more
Citations
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C9orf72 -mediated ALS and FTD: multiple pathways to disease
Rubika Balendra,Adrian M. Isaacs +1 more
TL;DR: It is suggested that a combination of upstream mechanisms involving both loss and gain of function and downstream cellular pathways involving both cell-aut autonomous and non-cell-autonomous effects contributes to disease progression.
Journal ArticleDOI
ALS Genetics, Mechanisms, and Therapeutics: Where Are We Now?
Rita Mejzini,Loren L. Flynn,Loren L. Flynn,Ianthe Pitout,Ianthe Pitout,Sue Fletcher,Sue Fletcher,Steve D. Wilton,Steve D. Wilton,P.A. Akkari,P.A. Akkari +10 more
TL;DR: The genetic basis of ALS is reviewed, highlighting factors that have contributed to the elusiveness of genetic heritability and future directions for research that may lead to effective treatment strategies outlined.
Journal ArticleDOI
The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy.
Christopher P. Webster,Emma F. Smith,Claudia S. Bauer,Annekathrin Moller,Guillaume M. Hautbergue,Laura Ferraiuolo,Monika A Myszczynska,Adrian Higginbottom,Matthew J. Walsh,Alexander J. Whitworth,Brian K. Kaspar,Kathrin Meyer,Pamela J. Shaw,Andrew J. Grierson,Kurt J. De Vos +14 more
TL;DR: The data identify C9orf72 as a novel Rab1a effector in the regulation of autophagy and indicate that C 9orf72 haploinsufficiency and associated reductions in Autophagy might be the underlying cause of C9ALS/FTD‐associated p62 pathology.
Journal ArticleDOI
The ALS/FTLD associated protein C9orf72 associates with SMCR8 and WDR41 to regulate the autophagy-lysosome pathway
Peter M. Sullivan,Xiaolai Zhou,Adam M. Robins,Daniel H. Paushter,Dongsung Kim,Marcus B. Smolka,Fenghua Hu +6 more
TL;DR: This study elucidates potential physiological functions of C9orf72 and disease mechanisms of ALS/FTLD and demonstrates that C 9orf72/SMCR8/WDR41 associates with the FIP200/Ulk1 complex, which is essential for autophagy initiation.
Journal ArticleDOI
Drosophila screen connects nuclear transport genes to DPR pathology in c9ALS/FTD
Steven Boeynaems,Elke Bogaert,Emiel Michiels,Ilse Gijselinck,Anne Sieben,Anne Sieben,Ana Jovičić,Greet De Baets,Greet De Baets,Wendy Scheveneels,Jolien Steyaert,Ivy Cuijt,Kevin J. Verstrepen,Patrick Callaerts,Frederic Rousseau,Frederic Rousseau,Joost Schymkowitz,Joost Schymkowitz,Marc Cruts,Christine Van Broeckhoven,Philip Van Damme,Aaron D. Gitler,Wim Robberecht,Ludo Van Den Bosch +23 more
TL;DR: Evidence is provided for an important role for nucleocytoplasmic transport in the pathogenic mechanism of c9ALS/FTD and for importins and exportins, Ran-GTP cycle regulators, nuclear pore components, and arginine methylases in mediating DPR toxicity.
References
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Journal ArticleDOI
El Escorial revisited : revised criteria for the diagnosis of amyotrophic lateral sclerosis
TL;DR: The criteria described below represent the result of a three-day workshop, convened at Airlie Conference Center, Warrenton, Virginia on 2–4 April, 1998 by the World Federation of Neurology Research Committee on Motor Neuron Diseases, and are placed on the WFN ALS website.
Journal ArticleDOI
Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS
Mariely DeJesus-Hernandez,Ian R. A. Mackenzie,Bradley F. Boeve,Adam L. Boxer,Matt Baker,Nicola J. Rutherford,Alexandra M. Nicholson,Ni Cole A. Finch,Heather C. Flynn,Jennifer Adamson,Naomi Kouri,Aleksandra Wojtas,Pheth Sengdy,Ging-Yuek Robin Hsiung,Anna Karydas,William W. Seeley,Keith A. Josephs,Giovanni Coppola,Daniel H. Geschwind,Zbigniew K. Wszolek,Howard Feldman,Howard Feldman,David S. Knopman,Ronald C. Petersen,Bruce L. Miller,Dennis W. Dickson,Kevin B. Boylan,Neill R. Graff-Radford,Rosa Rademakers +28 more
TL;DR: It is found that repeat expansion in C9ORF72 is a major cause of both FTD and ALS, suggesting multiple disease mechanisms.
Journal ArticleDOI
A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD
Alan E. Renton,Elisa Majounie,Adrian James Waite,Javier Simón-Sánchez,Javier Simón-Sánchez,Sara Rollinson,J. Raphael Gibbs,J. Raphael Gibbs,Jennifer C. Schymick,Hannu Laaksovirta,John C. van Swieten,John C. van Swieten,Liisa Myllykangas,Hannu Kalimo,Anders Paetau,Yevgeniya Abramzon,Anne M. Remes,Alice Kaganovich,Sonja W. Scholz,Sonja W. Scholz,Sonja W. Scholz,Jamie Duckworth,Jinhui Ding,Daniel W. Harmer,Dena G. Hernandez,Dena G. Hernandez,Janel O. Johnson,Janel O. Johnson,Kin Y. Mok,Mina Ryten,Danyah Trabzuni,Rita Guerreiro,Richard W. Orrell,James Neal,Alexandra Murray,J. P. Pearson,Iris E. Jansen,David Sondervan,Harro Seelaar,Derek J. Blake,Kate Young,Nicola Halliwell,Janis Bennion Callister,Greg Toulson,Anna Richardson,Alexander Gerhard,Julie S. Snowden,David M. A. Mann,David Neary,Mike A. Nalls,Terhi Peuralinna,Lilja Jansson,Veli-Matti Isoviita,Anna-Lotta Kaivorinne,Maarit Hölttä-Vuori,Elina Ikonen,Raimo Sulkava,Michael Benatar,Joanne Wuu,Adriano Chiò,Gabriella Restagno,Giuseppe Borghero,Mario Sabatelli,David Heckerman,Ekaterina Rogaeva,Lorne Zinman,Jeffrey D. Rothstein,Michael Sendtner,Carsten Drepper,Evan E. Eichler,Can Alkan,Ziedulla Abdullaev,Svetlana Pack,Amalia Dutra,Evgenia Pak,John Hardy,Andrew B. Singleton,Nigel Williams,Peter Heutink,Stuart Pickering-Brown,Huw R. Morris,Huw R. Morris,Huw R. Morris,Pentti J. Tienari,Bryan J. Traynor,Bryan J. Traynor +85 more
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.
Journal ArticleDOI
The C9orf72 GGGGCC Repeat Is Translated into Aggregating Dipeptide-Repeat Proteins in FTLD/ALS
Kohji Mori,Shih-Ming Weng,Thomas Arzberger,Stephanie May,Kristin Rentzsch,Elisabeth Kremmer,Bettina Schmid,Bettina Schmid,Hans A. Kretzschmar,Marc Cruts,Christine Van Broeckhoven,Christian Haass,Christian Haass,Dieter Edbauer,Dieter Edbauer +14 more
TL;DR: It is found that characteristic intracellular inclusions of misfolded proteins define C9orf72 pathology, but the core proteins of the majority of inclusions are still unknown, and a new class of proteins links a common genetic mutation to the predominant pathology in certain neurodegenerative diseases.
Journal ArticleDOI
Unconventional Translation of C9ORF72 GGGGCC Expansion Generates Insoluble Polypeptides Specific to c9FTD/ALS
Peter E.A. Ash,Kevin F. Bieniek,Tania F. Gendron,Thomas R. Caulfield,Wen Lang Lin,Mariely DeJesus-Hernandez,Marka van Blitterswijk,Karen Jansen-West,Joseph W. Paul,Rosa Rademakers,Kevin B. Boylan,Dennis W. Dickson,Leonard Petrucelli +12 more
TL;DR: The specificity of C9RANT for c9FTD/ALS is a potential biomarker for this most common cause of FTD and ALS and have significant implications for treatment strategies directed at RAN-translated peptides and their aggregation and the RNA structures necessary for their production.
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