Journal Article

DZNE-2020-01056

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Different CSF protein profiles in amyotrophic lateral sclerosis and frontotemporal dementia with C9orf72 hexanucleotide repeat expansion

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.DZNE* ; Jahn, H. ; Fassbender, K. ; Lauer, M. ; van der Ende, E. L. ; van Swieten, J. C. ; Volk, A. E. ; Ludolph, A. C. ; Otto, M.

2020
BMJ Publishing Group London

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Please use a persistent id in citations: doi:10.1136/jnnp-2019-322476

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.

Keyword(s): Adult (MeSH) ; Aged (MeSH) ; Amyotrophic Lateral Sclerosis: cerebrospinal fluid (MeSH) ; Amyotrophic Lateral Sclerosis: genetics (MeSH) ; Biomarkers: cerebrospinal fluid (MeSH) ; C9orf72 Protein: genetics (MeSH) ; DNA Repeat Expansion: genetics (MeSH) ; Female (MeSH) ; Frontotemporal Dementia: cerebrospinal fluid (MeSH) ; Frontotemporal Dementia: genetics (MeSH) ; Hexosaminidases: cerebrospinal fluid (MeSH) ; Humans (MeSH) ; Male (MeSH) ; Middle Aged (MeSH) ; Neurofilament Proteins: cerebrospinal fluid (MeSH) ; Proteome: analysis (MeSH) ; Single Molecule Imaging (MeSH)

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Contributing Institute(s):

1. Bonn Pre 2020 (Bonn Pre 2020)
2. U Clinical Researchers - München (U Clinical Researchers - München)

Research Program(s):

1. 344 - Clinical and Health Care Research (POF3-344) (POF3-344)

Appears in the scientific report 2020

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; National-Konsortium ; SCOPUS ; Web of Science Core Collection

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