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

Muqaku, Besnik; Dorst, Johannes; Wiesenfarth, Maximilian; Otto, Markus; Ludolph, Albert C; Oeckl, Patrick

doi:10.1038/s44321-025-00272-w

Article / Essay Mon Aug 11 2025 CC BY 4.0

published

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

Muqaku, Besnik ; Dorst, Johannes ; Wiesenfarth, Maximilian ; Otto, Markus ; Ludolph, Albert C ; Oeckl, Patrick

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. Systematic selection revealed a panel of eight novel peptide biomarker candidates for ALS (out of 33,605) derived from seven proteins. In the validation cohort, NFL, MAP1B, MYL1, and APOC1 peptides were upregulated, and peptides from CADM3, SCG1, and PENK were downregulated in ALS compared to Con. The peptides (except NFL) were not changed in other neurodegenerative diseases, including Alzheimer´s disease, frontotemporal dementia and Parkinson´s disease. 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.

Synopsis Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that affects motor neurons, leading to neuronal degeneration and muscle weakness/atrophy. There is a need for fluid biomarkers to support basic research, diagnosis and drug development in ALS. Peptidomic analysis identified 33,605 peptides in a discovery cohort, 56 of them changed in ALS compared to controls. This is the highest number of identified peptides in CSF of patients with neurodegenerative diseases. In a validation cohort, PRM analysis targeting eight peptides showed all of them changed. Protein-derived peptide sequences have never been reported before and are not accessible via standard proteomics. A neurodegeneration cohort consisting of Alzheimer´s disease (AD), behavioral variant frontotemporal dementia (bvFTD) and Parkinson´s disease (PD) patients revealed only NFL deregulated, indicating ALS specificity of peptide biomarker candidates. Eight peptides are derived from proteins that associate with several important processes in ALS, such as neurodegeneration, muscle weakness/atrophy, metabolic alteration as well as neuronal loss, synaptic dysfunction and/or dysregulation of vesicle transport.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that affects motor neurons, leading to neuronal degeneration and muscle weakness/atrophy. There is a need for fluid biomarkers to support basic research, diagnosis and drug development in ALS.