Different CSF protein profiles in amyotrophic lateral sclerosis and frontotemporal dementia with C9orf72 hexanucleotide repeat expansion. Issue 5 (4th March 2020)

• Record Type: Journal Article
• Authors: Barschke, Peggy; Oeckl, Patrick; Steinacker, Petra; Al Shweiki, MHD Rami; Weishaupt, Jochen H; Landwehrmeyer, G Bernhard; Anderl-Straub, Sarah; Weydt, Patrick; Diehl-Schmid, Janine; Danek, Adrian; Kornhuber, Johannes; Schroeter, Matthias L; Prudlo, Johannes; Jahn, Holger; Fassbender, Klaus; Lauer, Martin; van der Ende, Emma Louise; van Swieten, John Cornelis; Volk, Alexander E; Ludolph, Albert C; Otto, Markus
• Other Names: author non-byline.; Uttner Ingo author non-byline.; Arnim Christine A F von author non-byline.; Fliessbach Klaus author non-byline.; Foerstl Hans author non-byline.; Grimmer Timo author non-byline.; Kassubek Jan author non-byline.; Maler Juan M author non-byline.; Schneider Anja author non-byline.; Wiltfang Jens author non-byline.
• Is Part Of: Journal of neurology, neurosurgery and psychiatry. Volume 91:Issue 5(2020)
• Page Start: 503
• Page End: 511
• Publication Date: 2020-03-04
• Subjects: Neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; Psychiatry -- Periodicals; 616.8
• DOI: 10.1136/jnnp-2019-322476
• Languages: English
• ISSNs: 0022-3050

Abstract

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.