Different CSF protein profiles in amyotrophic lateral sclerosis and frontotemporal dementia with C9orf72 hexanucleotide repeat expansion
Open accessAbstract
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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Deep proteomic study by mass spectrometry revealed decreased NPTXR CSF levels in c9FTD compared with asymptomatic mutation carriers.
“Furthermore, deep proteomic study by mass spectrometry revealed decreased NPTXR CSF levels in c9FTD compared with asymptomatic mutation carriers.”
From Neuronal pentraxins as biomarkers of synaptic activity: from physiological functions to pathological changes in neurodegeneration (2022) · cites this paper as Barschke et al. 2020
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Amyotrophic Lateral Sclerosis: Neurochemical Biomarkers
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Multiplex Panel Detects Glial and Inflammatory Biomarker Signatures in Sporadic and C9orf72-ALS
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Self-citation
- Authors
- Barschke, P., Oeckl, P., Steinacker, P., Al Shweiki, M. R., Weishaupt, J. H., Landwehrmeyer, G. B., Anderl-Straub, S., Weydt, P., Diehl-Schmid, J., Danek, A., Kornhuber, J., Schroeter, M. L., Prudlo, J., Jahn, H., Fassbender, K., Lauer, M., van der Ende, E. L., van Swieten, J. C., Volk, A. E., Ludolph, A. C., & Otto, M.
- Affiliations
- Universität Ulm (DE)
- University of Bonn (DE)
- Ludwig-Maximilians-Universität München (DE)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- University Hospital Leipzig (DE)
- German Center for Neurodegenerative Diseases (DE)
- University Medical Center Hamburg-Eppendorf (DE)
- Saarland University (DE)
- University of Würzburg (DE)
- Corresponding author
- Otto, Markus
- ORCID
- Venue
- Journal of Neurology, Neurosurgery & Psychiatry
- Publisher
- BMJ
- Published
- 2020-03-04
- Volume
- 91
- Issue
- 5
- Pages
- 503-511
- ISSN
- 0022-3050 (ISSN-L)
- 1468-330X
- OpenAlex
- W3010640471
- Cited by
- 45
- References
- 41
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 3 · 2023: 9 · 2022: 13 · 2021: 9 · 2020: 4
- FWCI
- 3.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neurology Neurosurgery & Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- DZNE Pub (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Dioraphte foundation (1402 1300)
- the EU Joint Program–Neurodegenerative Disease Research (JPND) network (PreFrontALS: 733051042, PreFrontAls: 01ED1512)
- German Federal Ministry of Education and Research (FTLDc 01GI1007A)
- the Foundation of the State of Baden-Wurttemberg (D.3830)
- the German Research Foundation/DFG (SFB1279, VO2028/1-1)
- Medical Faculty of Ulm University (Bausteinprogramm LSBN.0123)
- Netherlands Organisation for Health Research and Development (RiMod-FTD: 733051024)
- Bluefield Project
- the Thierry Latran Foundation
- BIU (D.5009)
- Deltaplan Dementie (733050103, 733050813)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- amyotrophic lateral sclerosis, frontotemporal dementia, C9orf72, hexanucleotide repeat expansion, cerebrospinal fluid proteome, biomarkers, UCHL1, mutation carriers, disease outcome prediction, ubiquitination, autophagy, synaptic organization
- MeSH terms
- Single Molecule Imaging, C9orf72 Protein, Adult, Aged, Amyotrophic Lateral Sclerosis, Female, Hexosaminidases, Humans, Male, Middle Aged, Biomarkers, Neurofilament Proteins, Proteome, DNA Repeat Expansion, Frontotemporal Dementia
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