title: A data-driven approach links microglia to pathology and prognosis in amyotrophic lateral sclerosis.
abstract: 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.
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, 385A Glossop Road, Sheffield, UK. j.cooper-knock@sheffield.ac.uk.
authors.forename: Johnathan
authors.identifier: 0000-0002-0873-8689
authors.initials: J
authors.lastname: Cooper-Knock
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, 385A Glossop Road, Sheffield, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Green
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, 385A Glossop Road, Sheffield, UK.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Altschuler
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, 385A Glossop Road, Sheffield, UK.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Wei
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, 385A Glossop Road, Sheffield, UK.
authors.forename: Joanna J
authors.initials: JJ
authors.lastname: Bury
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, 385A Glossop Road, Sheffield, UK.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Heath
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, 385A Glossop Road, Sheffield, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Wyles
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, 385A Glossop Road, Sheffield, UK.
authors.forename: Catherine
authors.initials: C
authors.lastname: Gelsthorpe
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, 385A Glossop Road, Sheffield, UK.
authors.forename: J Robin
authors.initials: JR
authors.lastname: Highley
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, 385A Glossop Road, Sheffield, UK.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Lorente-Pons
authors.affiliation: Department of Genetics, University of Leicester, Leicester, UK.
authors.forename: Tim
authors.initials: T
authors.lastname: Beck
authors.affiliation: Biogen Inc, 115 Broadway, Cambridge, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Doyle
authors.affiliation: Biogen Inc, 115 Broadway, Cambridge, USA.
authors.forename: Karel
authors.initials: K
authors.lastname: Otero
authors.affiliation: Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, NIA, NIH, Bethesda, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Traynor
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, 385A Glossop Road, Sheffield, UK.
authors.forename: Janine
authors.initials: J
authors.lastname: Kirby
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, 385A Glossop Road, Sheffield, UK.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Shaw
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, 385A Glossop Road, Sheffield, UK. winhide@sheffield.ac.uk.|Department of Biostatistics, Harvard School of Public Health, Boston, USA. winhide@sheffield.ac.uk.
authors.forename: Winston
authors.initials: W
authors.lastname: Hide
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology
chemical_list: D015415:Biomarkers; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human
keywords: Amyotrophic lateral sclerosis; Biomarkers; Microglia; Neuropathology; TREM2; Transciptome