• Peggy Barschke, Patrick Oeckl, Petra Steinacker, Mhd Rami Al Shweiki, Jochen H Weishaupt, G Bernhard Landwehrmeyer, Sarah Anderl-Straub, Patrick Weydt, Janine Diehl-Schmid, Adrian Danek, Johannes Kornhuber, Matthias L Schroeter, Johannes Prudlo, Holger Jahn, Klaus Fassbender, Martin Lauer, Emma Louise van der Ende, John Cornelis van Swieten, Alexander E Volk, Albert C Ludolph, Markus Otto, and German FTLD consortium.
• Department of Neurology, Ulm University, Ulm, Baden-Württemberg, Germany.
• J. Neurol. Neurosurg. Psychiatr. 2020 May 1; 91 (5): 503-511.

ObjectivesThe 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.MethodsWe 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).ResultsIn 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.ConclusionsThis 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.© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

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