Poly‐GP in cerebrospinal fluid links C9orf72‐associated dipeptide repeat expression to the asymptomatic phase of ALS/FTD
Abstract The C9orf72 GGGGCC repeat expansion is a major cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). Non‐conventional repeat translation results in five dipeptide repeat proteins (DPRs), but their clinical utility, overall significance, and temporal course in the p...
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Springer Nature
2017-04-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201607486 |
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| author | Carina Lehmer Patrick Oeckl Jochen H Weishaupt Alexander E Volk Janine Diehl‐Schmid Matthias L Schroeter Martin Lauer Johannes Kornhuber Johannes Levin Klaus Fassbender Bernhard Landwehrmeyer German Consortium for Frontotemporal Lobar Degeneration Martin H Schludi Thomas Arzberger Elisabeth Kremmer Andrew Flatley Regina Feederle Petra Steinacker Patrick Weydt Albert C Ludolph Dieter Edbauer Markus Otto Adrian Danek Emily Feneberg Sarah Anderl‐Straub Christine von Arnim Holger Jahn Anja Schneider Manuel Maler Maryna Polyakova Lina Riedl Jens Wiltfang Georg Ziegler |
| author_facet | Carina Lehmer Patrick Oeckl Jochen H Weishaupt Alexander E Volk Janine Diehl‐Schmid Matthias L Schroeter Martin Lauer Johannes Kornhuber Johannes Levin Klaus Fassbender Bernhard Landwehrmeyer German Consortium for Frontotemporal Lobar Degeneration Martin H Schludi Thomas Arzberger Elisabeth Kremmer Andrew Flatley Regina Feederle Petra Steinacker Patrick Weydt Albert C Ludolph Dieter Edbauer Markus Otto Adrian Danek Emily Feneberg Sarah Anderl‐Straub Christine von Arnim Holger Jahn Anja Schneider Manuel Maler Maryna Polyakova Lina Riedl Jens Wiltfang Georg Ziegler |
| author_sort | Carina Lehmer |
| collection | DOAJ |
| description | Abstract The C9orf72 GGGGCC repeat expansion is a major cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). Non‐conventional repeat translation results in five dipeptide repeat proteins (DPRs), but their clinical utility, overall significance, and temporal course in the pathogenesis of c9ALS/FTD are unclear, although animal models support a gain‐of‐function mechanism. Here, we established a poly‐GP immunoassay from cerebrospinal fluid (CSF) to identify and characterize C9orf72 patients. Significant poly‐GP levels were already detectable in asymptomatic C9orf72 mutation carriers compared to healthy controls and patients with other neurodegenerative diseases. The poly‐GP levels in asymptomatic carriers were similar to symptomatic c9ALS/FTD cases. Poly‐GP levels were not correlated with disease onset, clinical scores, and CSF levels of neurofilaments as a marker for axonal damage. Poly‐GP determination in CSF revealed a C9orf72 mutation carrier in our cohort and may thus be used as a diagnostic marker in addition to genetic testing to screen patients. Presymptomatic expression of poly‐GP and likely other DPR species may contribute to disease onset and thus represents an alluring therapeutic target. |
| format | Article |
| id | doaj-art-48101d2464c042379d4ddcf8b0a5e918 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2017-04-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-48101d2464c042379d4ddcf8b0a5e9182025-08-20T03:46:21ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842017-04-019785986810.15252/emmm.201607486Poly‐GP in cerebrospinal fluid links C9orf72‐associated dipeptide repeat expression to the asymptomatic phase of ALS/FTDCarina Lehmer0Patrick Oeckl1Jochen H Weishaupt2Alexander E Volk3Janine Diehl‐Schmid4Matthias L Schroeter5Martin Lauer6Johannes Kornhuber7Johannes Levin8Klaus Fassbender9Bernhard Landwehrmeyer10German Consortium for Frontotemporal Lobar DegenerationMartin H Schludi11Thomas Arzberger12Elisabeth Kremmer13Andrew Flatley14Regina Feederle15Petra Steinacker16Patrick Weydt17Albert C Ludolph18Dieter Edbauer19Markus Otto20Adrian DanekEmily FenebergSarah Anderl‐StraubChristine von ArnimHolger JahnAnja SchneiderManuel MalerMaryna PolyakovaLina RiedlJens WiltfangGeorg ZieglerGerman Center for Neurodegenerative Diseases (DZNE) and Munich Cluster for System Neurology (SyNergy)Department of Neurology, Ulm University HospitalDepartment of Neurology, Ulm University HospitalInstitute of Human Genetics, University Medical Centre Hamburg‐EppendorfDepartment of Psychiatry and Psychotherapy, Technical University of MunichClinic for Cognitive Neurology, University Clinic LeipzigDepartment of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of WürzburgDepartment of Psychiatry and Psychotherapy, Friedrich‐Alexander‐University of Erlangen‐NurembergGerman Center for Neurodegenerative Diseases (DZNE) and Munich Cluster for System Neurology (SyNergy)Department of Neurology, Saarland UniversityDepartment of Neurology, Ulm University HospitalGerman Center for Neurodegenerative Diseases (DZNE) and Munich Cluster for System Neurology (SyNergy)German Center for Neurodegenerative Diseases (DZNE) and Munich Cluster for System Neurology (SyNergy)Institute of Molecular Immunology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)Monoclonal Antibody Core Facility and Research Group, Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)German Center for Neurodegenerative Diseases (DZNE) and Munich Cluster for System Neurology (SyNergy)Department of Neurology, Ulm University HospitalDepartment of Neurology, Ulm University HospitalDepartment of Neurology, Ulm University HospitalGerman Center for Neurodegenerative Diseases (DZNE) and Munich Cluster for System Neurology (SyNergy)Department of Neurology, Ulm University HospitalAbstract The C9orf72 GGGGCC repeat expansion is a major cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). Non‐conventional repeat translation results in five dipeptide repeat proteins (DPRs), but their clinical utility, overall significance, and temporal course in the pathogenesis of c9ALS/FTD are unclear, although animal models support a gain‐of‐function mechanism. Here, we established a poly‐GP immunoassay from cerebrospinal fluid (CSF) to identify and characterize C9orf72 patients. Significant poly‐GP levels were already detectable in asymptomatic C9orf72 mutation carriers compared to healthy controls and patients with other neurodegenerative diseases. The poly‐GP levels in asymptomatic carriers were similar to symptomatic c9ALS/FTD cases. Poly‐GP levels were not correlated with disease onset, clinical scores, and CSF levels of neurofilaments as a marker for axonal damage. Poly‐GP determination in CSF revealed a C9orf72 mutation carrier in our cohort and may thus be used as a diagnostic marker in addition to genetic testing to screen patients. Presymptomatic expression of poly‐GP and likely other DPR species may contribute to disease onset and thus represents an alluring therapeutic target.https://doi.org/10.15252/emmm.201607486amyotrophic lateral sclerosisbiomarkerC9orf72cerebrospinal fluidfrontotemporal dementia |
| spellingShingle | Carina Lehmer Patrick Oeckl Jochen H Weishaupt Alexander E Volk Janine Diehl‐Schmid Matthias L Schroeter Martin Lauer Johannes Kornhuber Johannes Levin Klaus Fassbender Bernhard Landwehrmeyer German Consortium for Frontotemporal Lobar Degeneration Martin H Schludi Thomas Arzberger Elisabeth Kremmer Andrew Flatley Regina Feederle Petra Steinacker Patrick Weydt Albert C Ludolph Dieter Edbauer Markus Otto Adrian Danek Emily Feneberg Sarah Anderl‐Straub Christine von Arnim Holger Jahn Anja Schneider Manuel Maler Maryna Polyakova Lina Riedl Jens Wiltfang Georg Ziegler Poly‐GP in cerebrospinal fluid links C9orf72‐associated dipeptide repeat expression to the asymptomatic phase of ALS/FTD EMBO Molecular Medicine amyotrophic lateral sclerosis biomarker C9orf72 cerebrospinal fluid frontotemporal dementia |
| title | Poly‐GP in cerebrospinal fluid links C9orf72‐associated dipeptide repeat expression to the asymptomatic phase of ALS/FTD |
| title_full | Poly‐GP in cerebrospinal fluid links C9orf72‐associated dipeptide repeat expression to the asymptomatic phase of ALS/FTD |
| title_fullStr | Poly‐GP in cerebrospinal fluid links C9orf72‐associated dipeptide repeat expression to the asymptomatic phase of ALS/FTD |
| title_full_unstemmed | Poly‐GP in cerebrospinal fluid links C9orf72‐associated dipeptide repeat expression to the asymptomatic phase of ALS/FTD |
| title_short | Poly‐GP in cerebrospinal fluid links C9orf72‐associated dipeptide repeat expression to the asymptomatic phase of ALS/FTD |
| title_sort | poly gp in cerebrospinal fluid links c9orf72 associated dipeptide repeat expression to the asymptomatic phase of als ftd |
| topic | amyotrophic lateral sclerosis biomarker C9orf72 cerebrospinal fluid frontotemporal dementia |
| url | https://doi.org/10.15252/emmm.201607486 |
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