TY  - JOUR
AU  - Barschke, Peggy
AU  - Oeckl, Patrick
AU  - Steinacker, Petra
AU  - Al Shweiki, MHD Rami
AU  - Weishaupt, Jochen H
AU  - Landwehrmeyer, G Bernhard
AU  - Anderl-Straub, Sarah
AU  - Weydt, Patrick
AU  - Diehl-Schmid, Janine
AU  - Danek, Adrian
AU  - Kornhuber, Johannes
AU  - Schroeter, Matthias L
AU  - Prudlo, Johannes
AU  - Jahn, Holger
AU  - Fassbender, Klaus
AU  - Lauer, Martin
AU  - van der Ende, Emma Louise
AU  - van Swieten, John Cornelis
AU  - Volk, Alexander E
AU  - Ludolph, Albert C
AU  - Otto, Markus
TI  - Different CSF protein profiles in amyotrophic lateral sclerosis and frontotemporal dementia with C9orf72 hexanucleotide repeat expansion
JO  - Journal of neurology, neurosurgery, and psychiatry
VL  - 91
IS  - 5
SN  - 0022-3050
CY  - London
PB  - BMJ Publishing Group
M1  - DZNE-2020-01056
SP  - 503-511
PY  - 2020
AB  - 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.
KW  - Adult
KW  - Aged
KW  - Amyotrophic Lateral Sclerosis: cerebrospinal fluid
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - Biomarkers: cerebrospinal fluid
KW  - C9orf72 Protein: genetics
KW  - DNA Repeat Expansion: genetics
KW  - Female
KW  - Frontotemporal Dementia: cerebrospinal fluid
KW  - Frontotemporal Dementia: genetics
KW  - Hexosaminidases: cerebrospinal fluid
KW  - Humans
KW  - Male
KW  - Middle Aged
KW  - Neurofilament Proteins: cerebrospinal fluid
KW  - Proteome: analysis
KW  - Single Molecule Imaging
LB  - PUB:(DE-HGF)16
C6  - pmid:32132225
DO  - DOI:10.1136/jnnp-2019-322476
UR  - https://pub.dzne.de/record/151071
ER  -