Journal ArticleDOI
Loss of function of C9orf72 causes motor deficits in a zebrafish model of amyotrophic lateral sclerosis
Sorana Ciura,Serena Lattante,Isabelle Le Ber,Morwena Latouche,Hervé Tostivint,Alexis Brice,Edor Kabashi +6 more
TLDR
A genetic model for ALS was developed to determine whether loss of function of the zebrafish orthologue of C9orf72 (zC 9orf72) leads to abnormalities in neuronal development.Abstract:
Objective: To define the role that repeat expansions of a GGGGCC hexanucleotide sequence of the C9orf72 gene play in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). A genetic model for ALS was developed to determine whether loss of function of the zebrafish orthologue of C9orf72 (zC9orf72) leads to abnormalities in neuronal development. Methods: C9orf72 mRNA levels were quantified in brain and lymphoblasts derived from FTLD and ALS=FTLD patients and in zebrafish. Knockdown of the zC9orf72 was performed using 2 specific antisense morpholino oligonucleotides to block transcription. Quantifications of spontaneous swimming and tactile escape response, as well as measurements of axonal projections from the spinal cord, were performed. Results: Significantly decreased expression of C9orf72 transcripts in brain and lymphoblasts was found in sporadic FTLD and ALS=FTLD patients with normal-size or expanded hexanucleotide repeats. The zC9orf72 is selectively expressed in the developing nervous system at developmental stages. Loss of function of the zC9orf72 transcripts causes both behavioral and cellular deficits related to locomotion without major morphological abnormalities. These deficits were rescued upon overexpression of human C9orf72 mRNA transcripts. Interpretation: Our results indicate C9orf72 haploinsufficiency could be a contributing factor in the spectrum of ALS=FTLD neurodegenerative disorders. Loss of function of the zebrafish orthologue of zC9orf72 expression in zebrafish is associated with axonal degeneration of motor neurons that can be rescued by expressing human C9orf72 mRNA, highlighting the specificity of the induced phenotype. These results reveal a pathogenic consequence of decreased C9orf72 levels, supporting a loss of function mechanism of disease. ANN NEUROL 2013;74:180–187read more
Citations
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Journal ArticleDOI
Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis.
TL;DR: It is presented the case here that these two processes are intimately linked, with disease-initiated perturbation of either leading to further deviation of both protein and RNA homeostasis through a feedforward loop including cell-to-cell prion-like spread that may represent the mechanism for relentless disease progression.
Journal ArticleDOI
RNA Toxicity from the ALS/FTD C9ORF72 Expansion Is Mitigated by Antisense Intervention
Christopher J. Donnelly,Ping Wu Zhang,Jacqueline T. Pham,Aaron R. Haeusler,Nipun A. Mistry,Svetlana Vidensky,Elizabeth L. Daley,Erin M. Poth,Benjamin Hoover,Daniel M. Fines,Nicholas J. Maragakis,Pentti J. Tienari,Leonard Petrucelli,Bryan J. Traynor,Bryan J. Traynor,Jiou Wang,Frank Rigo,C. Frank Bennett,Seth Blackshaw,Rita Sattler,Jeffrey D. Rothstein +20 more
TL;DR: Data indicate a toxic RNA gain-of-function mechanism as a cause of C9ORF72 ALS and provide candidate antisense therapeutics and candidate human pharmacodynamic markers for therapy.
Journal ArticleDOI
Targeting RNA Foci in iPSC-Derived Motor Neurons from ALS Patients with a C9ORF72 Repeat Expansion
Dhruv Sareen,Jacqueline G. O’Rourke,Pratap Meera,A. K. M. G. Muhammad,Sharday Grant,Megan Simpkinson,Shaughn Bell,Sharon Carmona,Loren Ornelas,Anais Sahabian,Tania F. Gendron,Leonard Petrucelli,Michael Baughn,John Ravits,Matthew B. Harms,Frank Rigo,C. Frank Bennett,Thomas S. Otis,Clive N. Svendsen,Robert H. Baloh +19 more
TL;DR: Findings support the idea that the buildup of “toxic” RNA containing the GGGGCC repeat contributes to the death of motor neurons in ALS, and suggest that antisense oligonucleotides targeting this transcript may be a strategy for treating ALS patients with the C9ORF72 repeat expansion.
Journal ArticleDOI
Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration
Clotilde Lagier-Tourenne,Michael Baughn,Frank Rigo,Shuying Sun,Patrick Liu,Hairi Li,Jie Jiang,Andrew T. Watt,Seung J. Chun,Melanie Katz,Jinsong Qiu,Ying Sun,Shuo-Chien Ling,Qiang Zhu,Magdalini Polymenidou,Kevin Drenner,Jonathan W. Artates,Melissa McAlonis-Downes,Sebastian Markmiller,Kasey R. Hutt,Donald P. Pizzo,Janet Cady,Matthew B. Harms,Robert H. Baloh,Scott R. VandenBerg,Gene W. Yeo,Xiang-Dong Fu,C. Frank Bennett,Don W. Cleveland,John Ravits +29 more
TL;DR: Sustained ASO-mediated lowering of C9orf72 RNAs throughout the CNS of mice is demonstrated to be well tolerated, producing no behavioral or pathological features characteristic of ALS/FTD and only limited RNA expression alterations.
Journal ArticleDOI
Antisense Proline-Arginine RAN Dipeptides Linked to C9ORF72-ALS/FTD Form Toxic Nuclear Aggregates that Initiate In Vitro and In Vivo Neuronal Death
Xinmei Wen,Wenzhi Tan,Thomas Westergard,Karthik Krishnamurthy,Shashirekha S. Markandaiah,Yingxiao Shi,Shaoyu Lin,Neil A. Shneider,John Monaghan,Udai Bhan Pandey,Piera Pasinelli,Justin K. Ichida,Davide Trotti +12 more
TL;DR: Interestingly, G4C2 transcript-mediated neurotoxicity synergizes with that of PR aggregates, suggesting convergence of mechanisms.
References
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Journal ArticleDOI
Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis
Manuela Neumann,Deepak M. Sampathu,Linda K. Kwong,Adam C. Truax,Matthew Micsenyi,Thomas T. Chou,Jennifer Bruce,Theresa Schuck,Murray Grossman,Christopher M. Clark,Leo McCluskey,Bruce L. Miller,Eliezer Masliah,Ian R. A. Mackenzie,Howard Feldman,Wolfgang Feiden,Hans A. Kretzschmar,John Q. Trojanowski,Virginia M.-Y. Lee +18 more
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.
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
High-resolution in situ hybridization to whole-mount zebrafish embryos
Christine Thisse,Bernard Thisse +1 more
TL;DR: This protocol describes ISH of digoxigenin-labeled antisense RNA probes to whole-mount zebrafish embryos and uses conditions that favor specific hybridization to complementary mRNA sequences in the tissue(s) expressing the corresponding gene.
Journal ArticleDOI
Molecular biology of amyotrophic lateral sclerosis: insights from genetics.
Piera Pasinelli,Robert H. Brown +1 more
TL;DR: An overview of the mechanisms for motor neuron death and the role of non-neuronal cells in ALS is presented and new insights are generated into the diverse molecular pathways involved in ALS pathogenesis.
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Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS
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RNA Toxicity from the ALS/FTD C9ORF72 Expansion Is Mitigated by Antisense Intervention
Christopher J. Donnelly,Ping Wu Zhang,Jacqueline T. Pham,Aaron R. Haeusler,Nipun A. Mistry,Svetlana Vidensky,Elizabeth L. Daley,Erin M. Poth,Benjamin Hoover,Daniel M. Fines,Nicholas J. Maragakis,Pentti J. Tienari,Leonard Petrucelli,Bryan J. Traynor,Bryan J. Traynor,Jiou Wang,Frank Rigo,C. Frank Bennett,Seth Blackshaw,Rita Sattler,Jeffrey D. Rothstein +20 more