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Proteomics in cerebrospinal fluid and spinal cord suggests UCHL1, MAP2 and GPNMB as biomarkers and underpins importance of transcriptional pathways in amyotrophic lateral sclerosis

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Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease and the proteins and pathways involved in the pathophysiology are not fully understood. Even less is known about the preclinical disease phase. To uncover new ALS-related proteins and pathways, we performed a comparative proteomic analysis in cerebrospinal fluid (CSF) of asymptomatic (n = 14) and symptomatic (n = 14) ALS mutation carriers and sporadic ALS patients (n = 12) as well as post-mortem human spinal cord tissue (controls: n = 7, ALS, n = 8). Using a CSF-optimized proteomic workflow, we identified novel (e.g., UCHL1, MAP2, CAPG, GPNMB, HIST1H4A, HIST1H2B) and well-described (e.g., NEFL, NEFH, NEFM, CHIT1, CHI3L1) protein level changes in CSF of sporadic and genetic ALS patients with enrichment of proteins related to transcription, cell cycle and lipoprotein remodeling (total protein IDs: 2303). No significant alteration was observed in asymptomatic ALS mutation carriers representing the prodromal disease phase. We confirmed UCHL1, MAP2, CAPG and GPNMB as novel biomarker candidates for ALS in an independent validation cohort of patients (n = 117) using multiple reaction monitoring. In spinal cord tissue, 292 out of 6810 identified proteins were significantly changed in ALS with enrichment of proteins involved in mRNA splicing and of the neurofilament compartment. In conclusion, our proteomic data in asymptomatic ALS mutation carriers support the hypothesis of a sudden disease onset instead of a long preclinical phase. Both CSF and tissue proteomic data indicate transcriptional pathways to be amongst the most affected. UCHL1, MAP2 and GPNMB are promising ALS biomarker candidates which might provide additional value to the established neurofilaments in patient follow-up and clinical trials.

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Acknowledgements

We are grateful to all the patients who participated in this study. We thank Stephen Meier for his excellent technical assistance. QPrESTs for MRM analysis were partly provided by Atlas Antibodies AB (Bromma, Sweden).

Funding

This study was supported by the EU Joint Programme-Neurodegenerative Diseases networks SOPHIA (01ED1202A), BiomarkAPD (01ED1203F) and PreFrontAls (01ED1512), the German Federal Ministry of Education and Research (FTLDc 01GI1007A, MND-Net 01GM1103A), the EU (NADINE 246513, FAIR-PARK II 633190), the German Research Foundation/DFG (SFB1279), the foundation of the state Baden-Württemberg (D.3830), Boehringer Ingelheim Ulm University BioCenter (D.5009) and the Thierry Latran Foundation. DRT receives grants from Fonds Wetenschappelijk Onderzoek (FWO) G0F8516 N, and C1-internal funds from KU Leuven (C14-17-107). The funding sources were not involved in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

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Authors and Affiliations

  1. Department of Neurology, Ulm University Hospital, Oberer Eselsberg 45, 89081, Ulm, Germany

    Patrick Oeckl, Patrick Weydt, Jochen H. Weishaupt, Albert C. Ludolph & Markus Otto

  2. Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn, Bonn, Germany

    Patrick Weydt

  3. Laboratory of Neuropathology, Institute of Pathology, Ulm University, Ulm, Germany

    Dietmar R. Thal

  4. Department of Imaging and Pathology, KU Leuven and Department of Pathology, UZ Leuven, Louvain, Belgium

    Dietmar R. Thal

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  1. Patrick Oeckl
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Contributions

Conception and design: PO, MO. Data acquisition, analysis and interpretation: PO, PW, DRT, JHW, ACL, MO. All authors substantially revised the manuscript.

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Correspondence to Markus Otto.

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Conflict of interest

PO, PW, JHW, ACL and MO report no conflict of interest. DRT received consultant honorary from GE-Healthcare (UK), and Covance Laboratories (UK), speaker honorary from Novartis Pharma AG (Switzerland), travel reimbursement from GE-Healthcare (UK) and UCB (Belgium) and collaborated with Novartis Pharma AG (Switzerland), Probiodrug (Germany), GE-Healthcare (UK), and Janssen Pharmaceutical Companies (Belgium).

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee (Ethics Committee of Ulm) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Oeckl, P., Weydt, P., Thal, D.R. et al. Proteomics in cerebrospinal fluid and spinal cord suggests UCHL1, MAP2 and GPNMB as biomarkers and underpins importance of transcriptional pathways in amyotrophic lateral sclerosis. Acta Neuropathol 139, 119–134 (2020). https://doi.org/10.1007/s00401-019-02093-x

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