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Thome Memorial Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2015,1]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To investigate miR\u2010155 in the SOD1 mouse model and human sporadic and familial amyotrophic lateral sclerosis (ALS).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>NanoString microRNA, microglia and immune gene profiles, protein mass spectrometry, and RNA\u2010seq analyses were measured in spinal cord microglia, splenic monocytes, and spinal cord tissue from SOD1 mice and in spinal cord tissue of familial and sporadic ALS. miR\u2010155 was targeted by genetic ablation or by peripheral or centrally administered anti\u2013miR\u2010155 inhibitor in SOD1 mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In SOD1 mice, we found loss of the molecular signature that characterizes homeostatic microglia and increased expression of miR\u2010155. There was loss of the microglial molecules\n                      <jats:italic>P2ry12<\/jats:italic>\n                      ,\n                      <jats:italic>Tmem119, Olfml3<\/jats:italic>\n                      , transcription factors\n                      <jats:italic>Egr1<\/jats:italic>\n                      ,\n                      <jats:italic>Atf3<\/jats:italic>\n                      ,\n                      <jats:italic>Jun<\/jats:italic>\n                      ,\n                      <jats:italic>Fos<\/jats:italic>\n                      , and\n                      <jats:italic>Mafb,<\/jats:italic>\n                      and the upstream regulators\n                      <jats:italic>Csf1r, Tgfb1,<\/jats:italic>\n                      and\n                      <jats:italic>Tgfbr1,<\/jats:italic>\n                      which are essential for microglial survival. Microglia biological functions were suppressed including phagocytosis. Genetic ablation of miR\u2010155 increased survival in SOD1 mice by 51 days in females and 27 days in males and restored the abnormal microglia and monocyte molecular signatures. Disease severity in SOD1 males was associated with early upregulation of inflammatory genes, including\n                      <jats:italic>Apoe<\/jats:italic>\n                      in microglia. Treatment of adult microglia with apolipoprotein E suppressed the M0\u2010homeostatic unique microglia signature and induced an M1\u2010like phenotype. miR\u2010155 expression was increased in the spinal cord of both familial and sporadic ALS. Dysregulated proteins that we identified in human ALS spinal cord were restored in SOD1\n                      <jats:sup>G93A<\/jats:sup>\n                      \/miR\u2010155\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      mice. Intraventricular anti\u2013miR\u2010155 treatment derepressed microglial miR\u2010155 targeted genes, and peripheral anti\u2013miR\u2010155 treatment prolonged survival.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>We found overexpression of miR\u2010155 in the SOD1 mouse and in both sporadic and familial human ALS. Targeting miR\u2010155 in SOD1 mice restores dysfunctional microglia and ameliorates disease. These findings identify miR\u2010155 as a therapeutic target for the treatment of ALS. ANN NEUROL 2015;77:75\u201399<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.24304","type":"journal-article","created":{"date-parts":[[2014,11,7]],"date-time":"2014-11-07T11:28:32Z","timestamp":1415359712000},"page":"75-99","source":"Crossref","is-referenced-by-count":333,"title":["Targeting mi\n                    <scp>R<\/scp>\n                    \u2010155 restores abnormal microglia and attenuates disease in\n                    <scp>SOD<\/scp>\n                    1 mice"],"prefix":"10.1002","volume":"77","author":[{"given":"Oleg","family":"Butovsky","sequence":"first","affiliation":[{"name":"Ann Romney Center for Neurologic Diseases Department of Neurology, Brigham and Women's Hospital, Harvard Medical School Boston MA"},{"name":"Evergrande Center for Immunologic Diseases Brigham and Women's Hospital, Harvard Medical School Boston MA 02112"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark 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