A data-driven approach links microglia to pathology and prognosis in amyotrophic lateral sclerosis.
journal contributionposted on 29.08.2019, 14:45 by J Cooper-Knock, C Green, G Altschuler, W Wei, JJ Bury, PR Heath, M Wyles, C Gelsthorpe, JR Highley, A Lorente-Pons, T Beck, K Doyle, K Otero, B Traynor, J Kirby, PJ Shaw, W Hide
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.
This work was supported in part by the European Community’s Seventh Framework Programme [FP7/2007-2013] under the EuroMOTOR project [grant agreement no 259867 to JK and PJS]. PJS is also supported as a National Institute for Health Research Senior Investigator and by the Medical Research Council. JCK is funded by a National Institutes for Health Research (NIHR) Clinical Lectureship in Neurology. ALP is funded by a Pathological Society of Great Britain PhD studentship award and a scholarship for postgraduate studies awarded by ‘la Caixa’ Foundation (Spain). JK has been funded by a Sheffield Hospitals Charitable Trust [grant no 131425]. This work was supported in part by the Intramural Research Programs of the NIH, National Institute on Aging [Z01-AG000949-02 to BJT]. BJT was also supported by the Agency of Toxic Substances and Disease Registry, Centre for Disease Control.
CitationActa Neuropathologica Communications, 5 (1), pp. 23
Author affiliation/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Genetics and Genome Biology
VersionVoR (Version of Record)
Published inActa Neuropathologica Communications
NotesThe gene expression CEL files are available at Gene Expression Omnibus (www.ncbi.nlm.nih.gov/geo/).
Amyotrophic lateral sclerosisBiomarkersMicrogliaNeuropathologyTREM2TransciptomeAdultAgedAged, 80 and overAmyotrophic Lateral SclerosisBrainCell LineCohort StudiesDisease ProgressionFemaleGenome-Wide Association StudyHumansLymphocytesMaleMembrane GlycoproteinsMiddle AgedMotor NeuronsPrognosisReceptors, ImmunologicSpinal Cord