Identification of a Unique miRNA Signature in CD14+/CD16- Blood-Monocytes in ALS Subjects Identical to That Observed in SOD Mice (IN9-2.002)

Abstract

Objective: To determine if there are unique microRNA signatures in peripheral Ly6C Hi monocytes in SOD1 mice and whether these signatures are present in ALS subjects. Background We previously identified a pro-inflammatory gene signature in Ly6C Hi monocytes in SOD1 mice and demonstrated that modulation of in Ly6C Hi monocytes prolonged survival. Design/Methods: Peripheral blood monocyte subsets from 18 sALS, 4 fALS, 8 MS-RR, 13 AD and 33 age-matched controls were studied using Nanostring and miRNA arrays. Results: In SOD1 mice, microRNA analysis showed differential activation of splenic Ly6C HI vs. Ly6C Low two months prior to disease onset and during all stages of disease. The inflammation-related miRNAs let-7a, miR27a, miR-34a, miR-132 mir-146a, miR-451 and mir-155 were upregulated in splenic Ly6C Hi monocytes. Pathway analysis of the miRNA profile of Ly6C Hi monocytes in SOD1 mice identified patterns observed in primary muscular disorders. In humans with both sALS and fALS, CD14 + /CD16 - monocytes (the human analogue of Ly6C Hi monocytes) exhibited a pro-inflammatory phenotype similar to SOD1 mice as measured by both microRNA and gene expression profiling. 20 upregulated and 20 downregulated miRNAs were unique to ALS and distinguished ALS from controls and subjects with MS or AD. 32 dysregulated miRNAs were similar between ALS and MS; there was no overlap between ALS and AD. These results are consistent with our findings in the SOD1 mice of prominent changes in the Ly6C Hi monocytes. Conclusions: 1) Identification of identical microRNA abnormalities in monocytes of ALS as was found in SOD1 mice provide a direct link between the animal model and the human disease 2) This unique monocyte microRNA profile in ALS provides the basis for the development of a blood biomarker to monitor disease progression and response to therapy. 3) Modulation of the human analogue of Ly6C Hi monocytes provides a new target for ALS treatment. Supported by: 1. Prize4Life. 2.The Amyotrophic Lateral Sclerosis Association. Disclosure: Dr. Butovsky has nothing to disclose. Dr. Siddiqui has nothing to disclose. Dr. Gabriely has nothing to disclose. Dr. Lanser has nothing to disclose. Dr. Dake has nothing to disclose. Dr. Gopal has nothing to disclose. Dr. Doykan has nothing to disclose. Dr. Wu has nothing to disclose. Dr. Lawson has nothing to disclose. Dr. Berry has nothing to disclose. Dr. Krichevsky has nothing to disclose. Dr. Cudkowicz has received personal compensation for activities with Synapse, Trophos, and Acclerson as a data safety monitoring board chair or an advisory board member. Dr. Weiner has received personal compensation for activities with Biogen Idec, Novartis, Serono, Inc., Teva Neurosciences, GlaxoSmithKline, Nasvax, Xenoport and Genzyme Corporation as consulting and/or speaking activities. Dr. Weiner has received research support from Merck Serono.