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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Correction notice This article has been corrected since it was published Online First. Author name Patrick Oeckl has been corrected.
Collaborators FTLD consortium: Ingo Uttner, PhD; Christine AF von Arnim, MD; Klaus Fliessbach, MD; Hans Foerstl, MD; Timo Grimmer, MD; Jan Kassubek, MD; Juan M Maler, MD; Anja Schneider, MD; Jens Wiltfang, MD.
Contributors Concept and design: PB, PO, PS, MHDRAS, MO; Statistical analysis: PB; Drafting of the manuscript: PB, PO, MO; Obtained funding: JD-S, AD, JK, MLS, JP, HJ, KF, ML, JCvS, AEV, ACL, MO; Supervision: MO; Methodology: PB, PO, and MHDRAS; Acquisition, analysis, and/or interpretation of the data: PB, PO, PS, MHDRAS, MO; Patient recruitment: JHW, BL, SA-S, PW, JD-S, AD, JK, MLS, JP, HJ, KF, ML, ELvdE, JCvS, ACL, MO; All authors participated in the critical review of the manuscript and approved the submitted version.
Funding The study was supported by grants from the German Federal Ministry of Education and Research (project: FTLDc 01GI1007A), the EU Joint Programme–Neurodegenerative Disease Research (JPND) network, PreFrontAls (01ED1512), the Foundation of the State of Baden-Wurttemberg (D.3830), the Thierry Latran Foundation, BIU (D.5009), the German Research Foundation/DFG (SFB1279 and VO2028/1-1) and the Medical Faculty of Ulm University (Bausteinprogramm LSBN.0123), in the Netherlands by two Memorabel grants from Deltaplan Dementie (The Netherlands Organisation for Health Research and Development and Alzheimer Nederland; grant numbers 733050813 and 733050103), the Dioraphte foundation (grant number 14021300) the Bluefield Project and the European JPND and the Netherlands Organisation for Health Research and Development (PreFrontALS: 733051042, RiMod-FTD: 733051024).
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. Raw data will be available on request.
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