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Different CSF protein profiles in amyotrophic lateral sclerosis and frontotemporal dementia with C9orf72
Peggy Barschke1, Patrick Oeckl1, Petra Steinacker1
1Department of Neurology, Ulm University, Ulm, Baden-Württemberg, Germany.
Insights
Researchers identified cerebrospinal fluid (CSF) protein biomarkers to distinguish between C9-ALS and C9-FTD. Elevated UCHL1 in C9-ALS and reduced NPTXR in C9-FTD may indicate disease pathways.
Area of Science:
- Neuroscience
- Genetics
- Proteomics
Background:
- The C9orf72 gene hexanucleotide repeat expansion is the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
- Distinguishing between C9-ALS and C9-FTD in mutation carriers remains a clinical challenge.
- Identifying cerebrospinal fluid (CSF) biomarkers could aid in differentiating these neurodegenerative conditions.
Purpose of the Study:
- To identify protein biomarker candidates in CSF that differentiate C9-ALS from C9-FTD.
- To investigate potential indicators of disease outcome in C9orf72 mutation carriers.
- To explore the functional implications of identified biomarker differences.
Main Methods:
- Comparative proteomic analysis of CSF from C9-ALS, C9-FTD patients, and asymptomatic carriers using isobaric tags for relative and absolute quantitation (iTRAQ).
- Selection of differentially regulated proteins for validation using multiple reaction monitoring (MRM) and single-molecule array (Simoa) in a larger cohort (n=156).
- Identification of 2095 CSF proteins, with 236 showing significant differences between C9-ALS and C9-FTD.
Main Results:
- Neurofilament medium polypeptide (NEFM) and chitotriosidase-1 (CHIT1) levels were significantly higher in C9-ALS compared to C9-FTD.
- Ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1) levels were significantly increased in C9-ALS versus C9-FTD and controls.
- Neuronal pentraxin receptor (NPTXR) levels were decreased in C9-FTD compared to asymptomatic carriers.
Conclusions:
- This deep proteomic CSF analysis provides novel insights into the molecular differences between C9-ALS and C9-FTD.
- Elevated CSF UCHL1 in C9-ALS may reflect altered ubiquitination and autophagy processes.
- Decreased CSF NPTXR in C9-FTD might indicate distinct synaptic organization processes.
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.
