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@ARTICLE{Barschke:151071,
author = {Barschke, Peggy and Oeckl, Patrick and Steinacker, Petra
and Al Shweiki, MHD Rami and Weishaupt, Jochen H and
Landwehrmeyer, G Bernhard and Anderl-Straub, Sarah and
Weydt, Patrick and Diehl-Schmid, Janine and Danek, Adrian
and Kornhuber, Johannes and Schroeter, Matthias L and
Prudlo, Johannes and Jahn, Holger and Fassbender, Klaus and
Lauer, Martin and van der Ende, Emma Louise and van Swieten,
John Cornelis and Volk, Alexander E and Ludolph, Albert C
and Otto, Markus},
title = {{D}ifferent {CSF} protein profiles in amyotrophic lateral
sclerosis and frontotemporal dementia with {C}9orf72
hexanucleotide repeat expansion},
journal = {Journal of neurology, neurosurgery, and psychiatry},
volume = {91},
number = {5},
issn = {0022-3050},
address = {London},
publisher = {BMJ Publishing Group},
reportid = {DZNE-2020-01056},
pages = {503-511},
year = {2020},
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.},
keywords = {Adult / Aged / Amyotrophic Lateral Sclerosis: cerebrospinal
fluid / Amyotrophic Lateral Sclerosis: genetics /
Biomarkers: cerebrospinal fluid / C9orf72 Protein: genetics
/ DNA Repeat Expansion: genetics / Female / Frontotemporal
Dementia: cerebrospinal fluid / Frontotemporal Dementia:
genetics / Hexosaminidases: cerebrospinal fluid / Humans /
Male / Middle Aged / Neurofilament Proteins: cerebrospinal
fluid / Proteome: analysis / Single Molecule Imaging},
cin = {Bonn Pre 2020 / U Clinical Researchers - München},
ddc = {610},
cid = {I:(DE-2719)6000011 / I:(DE-2719)7000003},
pnm = {344 - Clinical and Health Care Research (POF3-344)},
pid = {G:(DE-HGF)POF3-344},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:32132225},
doi = {10.1136/jnnp-2019-322476},
url = {https://pub.dzne.de/record/151071},
}