A data-driven approach links microglia to pathology and prognosis in amyotrophic lateral sclerosis
Open accessAbstract
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that lacks a predictive and broadly applicable biomarker. Continued focus on mutation-specific upstream mechanisms has yet to predict disease progression in the clinic. Utilising cellular pathology common to the majority of ALS patients, we implemented an objective transcriptome-driven approach to develop noninvasive prognostic biomarkers for disease progression. Genes expressed in laser captured motor neurons in direct correlation (Spearman rank correlation, p < 0.01) with counts of neuropathology were developed into co-expression network modules. Screening modules using three gene sets representing rate of disease progression and upstream genetic association with ALS led to the prioritisation of a single module enriched for immune response to motor neuron degeneration. Genes in the network module are important for microglial activation and predict disease progression in genetically heterogeneous ALS cohorts: Expression of three genes in peripheral lymphocytes - LILRA2, ITGB2 and CEBPD - differentiate patients with rapid and slowly progressive disease, suggesting promise as a blood-derived biomarker. TREM2 is a member of the network module and the level of soluble TREM2 protein in cerebrospinal fluid is shown to predict survival when measured in late stage disease (Spearman rank correlation, p = 0.01). Our data-driven systems approach has, for the first time, directly linked microglia to the development of motor neuron pathology. LILRA2, ITGB2 and CEBPD represent peripherally accessible candidate biomarkers and TREM2 provides a broadly applicable therapeutic target for ALS.
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Human genome-wide association studies have implicated mutations in microglial receptors in the development of several neurodegenerative diseases.
“Indeed, human genome-wide association studies (GWAS) have implicated mutations in microglial receptors in the development of several neurodegenerative diseases (Cooper-Knock et al., 2017; Efthymiou and Goate, 2017; IMSG, 2019).”
From SYK coordinates neuroprotective microglial responses in neurodegenerative disease (2022) · cites this paper as Cooper-Knock et al., 2017
The Discussion (page unavailable) says that loss-of-function mutations in the microglial receptor TREM2 have been linked to risk of both Alzheimer’s disease and ALS. It also reports GWAS-gene enrichment for those diseases, but does not say that GWAS implicated mutations in multiple microglial receptors. (LLM, conf=0.86)
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- Authors
- Cooper-Knock, J., Green, C., Altschuler, G., Wei, W., Bury, J. J., Heath, P. R., Wyles, M., Gelsthorpe, C., Highley, J. R., Lorente-Pons, A., Beck, T., Doyle, K., Otero, K., Traynor, B., Kirby, J., Shaw, P. J., & Hide, W.
- Affiliations
- University of Sheffield (GB)
- University of Leicester (GB)
- Biogen (United States) (US)
- National Institutes of Health (US)
- Harvard University (US)
- Corresponding author
- Hide, Winston
- ORCID
- Venue
- Acta Neuropathologica Communications
- Published
- 2017-03-16
- Volume
- 5
- Issue
- 1
- Pages
- 23-23
- ISSN
- 2051-5960 (ISSN-L)
- PMC
- PMC5353945
- OpenAlex
- W2596238655
- Cited by
- 80
- References
- 56
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 5 · 2023: 12 · 2022: 16 · 2021: 8 · 2020: 8 · 2019: 6 · 2018: 10 · 2017: 3
- FWCI
- 5.14
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Acta Neuropathologica Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Figshare (submittedVersion, cc-by)
- Leicester Research Archive (University of Leicester) (submittedVersion, cc-by)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, cc-by)
- Funders
- Seventh Framework Programme (FP7/2007-2013)
- National Institute for Health Research
- Pathological Society of Great Britain and Ireland
- “la Caixa” Foundation
- Sheffield Hospitals Charity (131425)
- National Institute on Aging (Z01-AG000949-02)
- Agency of Toxic Substances and Disease Registry
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Keywords
- amyotrophic lateral sclerosis, microglia, disease progression, prognostic factors, transcriptome, motor neuron degeneration, immune response, CD18, CEBPD, TREM2, soluble TREM2, cerebrospinal fluid, peripheral blood biomarkers, survival prediction, therapeutic target
- MeSH terms
- Adult, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, Brain, Cell Line, Female, Humans, Lymphocytes, Male, Membrane Glycoproteins, Middle Aged, Motor Neurons, Prognosis, Receptors, Immunologic, Spinal Cord, Cohort Studies, Biomarkers, Microglia, Disease Progression, Genome-Wide Association Study
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