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  Different CSF protein profiles in amyotrophic lateral sclerosis and frontotemporal dementia with C9orf72 hexanucleotide repeat expansion

Barschke, P., Oeckl, P., Steinacker, P., Shweiki, M. R. A., Weishaupt, J. H., Landwehrmeyer, G. B., et al. (2020). Different CSF protein profiles in amyotrophic lateral sclerosis and frontotemporal dementia with C9orf72 hexanucleotide repeat expansion. Journal of Neurology, Neurosurgery & Psychiatry, 91(5), 503-511. doi:10.1136/jnnp-2019-322476.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0006-9267-1 Version Permalink: http://hdl.handle.net/21.11116/0000-0006-9268-0
Genre: Journal Article

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 Creators:
Barschke, Peggy1, Author
Oeckl, Patrick1, Author
Steinacker, Petra1, Author
Shweiki, Mhd Rami Al1, Author
Weishaupt, Jochen H.1, Author
Landwehrmeyer, G. Bernhard1, Author
Anderl-Straub, Sarah1, Author
Weydt, Patrick2, Author
Diehl-Schmid, Janine3, Author
Danek, Adrian4, Author
Kornhuber, Johannes5, Author
Schroeter, Matthias L.6, 7, Author              
Prudlo, Johannes8, Author
Jahn, Holger9, Author
Fassbender, Klaus10, Author
Lauer, Martin11, Author
van der Ende, Emma Louise12, Author
van Swieten, John Cornelis12, Author
Volk, Alexander E.13, Author
Ludolph, Albert C.1, Author
Otto, Markus1, AuthorGerman FTLD Consortium, Author               more..
Affiliations:
1Department of Neurology, Ulm University, Germany, ou_persistent22              
2Department of Neurodegenerative Disease and Geriatric Psychiatry, University Hospital Bonn, Germany, ou_persistent22              
3Department of Psychiatry and Psychotherapy, Ludwig Maximilians University Munich, Germany, ou_persistent22              
4Neurologische Klinik und Poliklinik, Ludwig Maximilians University Munich, Germany, ou_persistent22              
5Department of Psychology and Psychotherapy, Friedrich Alexander University Erlangen, Germany, ou_persistent22              
6Department Neurology, MPI for Human Cognitive and Brain Sciences, Max Planck Society, ou_634549              
7Clinic for Cognitive Neurology, University of Leipzig, Germany, ou_persistent22              
8German Center for Neurodegenerative Diseases, Rostock, Germany, ou_persistent22              
9Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf, Germany, ou_persistent22              
10Department of Neurology, Saarland University Homburg, Germany, ou_persistent22              
11Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Germany, ou_persistent22              
12Department of Neurology, Erasmus University Rotterdam, the Netherlands, ou_persistent22              
13Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Germany, ou_persistent22              

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 Abstract: Objectives: The hexanucleotide repeat expansion in the C9orf72 gene is the most common mutation associated with amyotrophic lateral sclerosis (C9-ALS) and frontotemporal dementia (C9-FTD). Until now, it is unknown which factors define whether C9orf72 mutation carriers develop ALS or FTD. Our aim was to identify protein biomarker candidates in the cerebrospinal fluid (CSF) which differentiate between C9-ALS and C9-FTD and might be indicative for the outcome of the mutation. Methods: We compared the CSF proteome of 16 C9-ALS and 8 C9-FTD patients and 11 asymptomatic C9orf72 mutation carriers (CAR) by isobaric tags for relative and absolute quantitation. Eleven biomarker candidates were selected from the pool of differentially regulated proteins for further validation by multiple reaction monitoring and single-molecule array in a larger cohort (n=156). Results: In total, 2095 CSF proteins were identified and 236 proteins were significantly different in C9-ALS versus C9-FTD including neurofilament medium polypeptide (NEFM) and chitotriosidase-1 (CHIT1). Eight candidates were successfully validated including significantly increased ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1) levels in C9-ALS compared with C9-FTD and controls and decreased neuronal pentraxin receptor (NPTXR) levels in C9-FTD versus CAR. Conclusions: This study presents a deep proteomic CSF analysis of C9-ALS versus C9-FTD patients. As a proof of concept, we observed higher NEFM and CHIT1 CSF levels in C9-ALS. In addition, we also show clear upregulation of UCHL1 in C9-ALS and downregulation of NPTXR in C9-FTD. Significant differences in UCHL1 CSF levels may explain diverging ubiquitination and autophagy processes and NPTXR levels might reflect different synapses organisation processes.

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Language(s): eng - English
 Dates: 2020-03-042020-05
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1136/jnnp-2019-322476
Other: epub 2020
PMID: 32132225
 Degree: -

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Project name : -
Grant ID : -
Funding program : (FTLDc 01GI1007A)
Funding organization : German Federal Ministry of Education and Research
Project name : -
Grant ID : -
Funding program : (01ED1512)
Funding organization : EU Joint Programme–Neurodegenerative Disease Research (JPND) network
Project name : -
Grant ID : -
Funding program : (D.3830)
Funding organization : Foundation of the State of Baden-Wurttemberg
Project name : -
Grant ID : -
Funding program : (D.5009)
Funding organization : Thierry Latran Foundation
Project name : -
Grant ID : -
Funding program : (SFB1279)
Funding organization : German Research Foundation/DFG
Project name : -
Grant ID : -
Funding program : (VO2028/1-1)
Funding organization : German Research Foundation/DFG
Project name : -
Grant ID : -
Funding program : (LSBN.0123)
Funding organization : Medical Faculty of Ulm University
Project name : -
Grant ID : 733050813
Funding program : -
Funding organization : Netherlands Organisation for Health Research and Development
Project name : -
Grant ID : 733050103
Funding program : -
Funding organization : Alzheimer Nederland
Project name : -
Grant ID : -
Funding program : (14021300)
Funding organization : Dioraphte foundation
Project name : Bluefield Project
Grant ID : -
Funding program : (733051042)
Funding organization : -
Project name : European JPND
Grant ID : -
Funding program : (733051024)
Funding organization : -

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Title: Journal of Neurology, Neurosurgery & Psychiatry
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: London : British Medical Association
Pages: - Volume / Issue: 91 (5) Sequence Number: - Start / End Page: 503 - 511 Identifier: ISSN: 0022-3050
CoNE: https://pure.mpg.de/cone/journals/resource/111085522793000