A data-driven approach links microglia to pathology and prognosis in amyotrophic lateral sclerosis
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Author
Cooper-Knock, Johnathan
Green, Claire
Altschuler, Gabriel
Wei, Wenbin
Bury, Joanna J.
Heath, Paul R.
Wyles, Matthew
Gelsthorpe, Catherine
Highley, J. Robin
Lorente-Pons, Alejandro
Beck, Tim
Doyle, Kathryn
Otero, Karel
Traynor, Bryan
Kirby, Janine
Shaw, Pamela J.
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1186/s40478-017-0424-xMetadata
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Cooper-Knock, J., C. Green, G. Altschuler, W. Wei, J. J. Bury, P. R. Heath, M. Wyles, et al. 2017. “A data-driven approach links microglia to pathology and prognosis in amyotrophic lateral sclerosis.” Acta Neuropathologica Communications 5 (1): 23. doi:10.1186/s40478-017-0424-x. http://dx.doi.org/10.1186/s40478-017-0424-x.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. Electronic supplementary material The online version of this article (doi:10.1186/s40478-017-0424-x) contains supplementary material, which is available to authorized users.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5353945/pdf/Terms of Use
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