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Peptidomic analysis of CSF reveals new biomarker candidates for amyotrophic lateral sclerosis

ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease and novel biomarkers are needed. We applied mass-spectrometry-based peptidomic analysis in cerebrospinal fluid (CSF) samples of ALS and non-neurodegenerative control patients (Con) from a discovery (n=48) and validation (n=109) cohort for biomarker discovery. We identified 33605 peptides in CSF samples from the discovery cohort. Systematic selection for the best candidates revealed a targeted method with eight peptides derived from seven proteins. In the validation cohort, NFL, MAP1B, MYL1, APOC1 peptides were up-regulated and peptides from CADM3, SCG1 and PENK down-regulated in ALS compared to Con. Combination of all peptides in a logistic regression model led to an area under the curve value of 98% for the discrimination of ALS from controls. Data of the NFL peptide strongly correlated with an established NFL immunoassay (Ella, r=0.97). The peptide biomarker candidates are derived from proteins with different function and their determination with our method provides the opportunity for simultaneous investigation of key processes in ALS and other neurodegenerative diseases.

INSTRUMENT(S): Orbitrap Exploris 480, FAIMS compensation voltage

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cerebrospinal Fluid

DISEASE(S): Amyotrophic Lateral Sclerosis

SUBMITTER: Besnik Muqaku

LAB HEAD: Patrick Oeckl

PROVIDER: PXD062419 | Pride | 2025-06-26

REPOSITORIES: Pride

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			Action	DRS
	DiscoveryCohort.mzid	Mzid
	DiscoveryCohort_LFQ.csv	Csv
	DiscoveryCohort_QC.mzid	Mzid
	DiscoveryCohort_QC1.mgf	Mgf
	DiscoveryCohort_QC1.raw	Raw

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Discovery of biomarkers for amyotrophic lateral sclerosis from human cerebrospinal fluid using mass spectrometry-based proteomics

Project description:Amyotrophic lateral sclerosis (ALS) is progressive neurodegenerative diseases characterized by the relentless loss of upper and lower motor neurons, eventually leading to death. Critical to the mission of developing effective therapies for ALS is the discovery of biomarkers that can illuminate mechanisms of neurodegeneration, as well as that, can be used for diagnostic, prognostic, or pharmacodynamic value across the disease. Here, we merged unbiased discovery-based approaches and targeted quantitative comparative analyses to identify proteins that are altered in cerebrospinal fluid (CSF) from ALS. Mass spectrometry (MS)-based proteomic approaches employing tandem mass tags (TMT) quantification methods from 40 CSF samples comprising 20 patients with ALS and 20 healthy control (HC) individuals identified 53 candidate biomarker proteins after CSF fractionation. Notably, these candidate biomarkers included both previously identified proteins validating our approach and novel ones, expanding the applicability of the biomarkers. Candidate biomarkers were subsequently examined using parallel reaction monitoring (PRM) MS methods on 61 unfractionated CSF samples comprising 30 patients with ALS and 31 HC individuals. Fifteen candidate biomarkers (APOB, APP, CAMK2A, CHI3L1, CHIT1, CLSTN3, ERAP2, FSTL4, GPNMB, JCHAIN, L1CAM, NPTX2, SERPINA1, SERPINA3 and UCHL1) showed significant differences between ALS and Control. Taken together, this study identifies multiple novel proteins that are altered in ALS, which provides the foundation for developing biomarkers for ALS.

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Project description:Amyotrophic lateral sclerosis (ALS) is a clinical subtype of motor neurone disease (MND), a fatal neurodegenerative disease involving the loss of both the upper and lower motor neurones from the motor cortex, brainstem, and spinal cord. Identifying specific disease biomarkers would help to not only improve diagnostic delay but also to classify disease subtypes, monitor response to therapeutic drugs and track disease progression. miRNAs are small non-coding RNA responsible for regulating gene expression and ultimately protein expression and have been used as biomarkers for many cancers and neurodegenerative disorders. Investigating the detection of miRNAs in cerebrospinal fluid (CSF), the fluid that bathes the central nervous system (CNS) is a prime target for identifying potential biomarkers for ALS. This is the first study to investigate the expression of miRNAs in the CSF of ALS patients using small RNA sequencing. We detected differentially expressed miRNAs in the CSF of sporadic ALS (sALS) patients related to neural and glial activity. Additionally, miRNAs involved in glucose metabolism and the regulation of oxidative stress were also identified. Detecting the presence of potential CSF derived miRNA biomarkers in sALS could open up a whole new area of knowledge to help gain a better understanding of disease pathophysiology.

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CSF chitinase 3-like 2 is associated with disability progression in patients with progressive multiple sclerosis

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