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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-017-0424-x) contains supplementary material, which is available to authorized users.

Changes in Retinal OCT and Their Correlations with Neurological Disability in Early ALS Patients, a Follow-Up Study

“…This macular increased thickness has also been found in other neurodegenerative diseases such as early Alzheimer disease (AD) [34] or Down's syndrome [31]. We hypothesize that the significant increase in MT in temporal and inferior IMR areas observed in our ALS patients could be caused by a process of protein aggregation [42,52] and/or neuroinflammation, in which microglia have an important role in ALS pathogenesis [56]. Activated microglia exhibit morphological changes (retraction of processes and enlargement of the soma), migrate, and proliferate.…”

Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomized clinical trial

“…Additional disease mechanisms offer another explanation for relative lack of efficacy in "Fast Progressor" patients, with targeted therapies expected to work on only a subset of ALS patients. Indeed, gene expression profiling and proteomic studies in ALS have successfully differentiated patients with rapid and non-rapid progressive disease (the latter defined as having an equivalent DFS of around 1.0 point/month) (19,(28)(29)(30)(31), such evidence supporting the premise that these groups represent pathophysiologically distinct forms of ALS.…”

Microglia in Multiple Sclerosis: Friend or Foe?

“…Aside from the genetic diseases mentioned above, microglia have increasingly been implicated in neurodegenerative diseases, including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and multiple sclerosis (17)(18)(19)(20)(21). Within the context of MS, "classically activated" microglia are thought to be critical for phagocytosis of myelin, antigen presentation to T cells and release of proinflammatory cytokines in active lesions (22).…”