Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice.
OBJECTIVE
To investigate miR-155 in the SOD1 mouse model and human sporadic and familial amyotrophic lateral sclerosis (ALS).


METHODS
NanoString microRNA, microglia and immune gene profiles, protein mass spectrometry, and RNA-seq 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-155 was targeted by genetic ablation or by peripheral or centrally administered anti-miR-155 inhibitor in SOD1 mice.


RESULTS
In SOD1 mice, we found loss of the molecular signature that characterizes homeostatic microglia and increased expression of miR-155. There was loss of the microglial molecules P2ry12, Tmem119, Olfml3, transcription factors Egr1, Atf3, Jun, Fos, and Mafb, and the upstream regulators Csf1r, Tgfb1, and Tgfbr1, which are essential for microglial survival. Microglia biological functions were suppressed including phagocytosis. Genetic ablation of miR-155 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 Apoe in microglia. Treatment of adult microglia with apolipoprotein E suppressed the M0-homeostatic unique microglia signature and induced an M1-like phenotype. miR-155 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(G93A) /miR-155(-/-) mice. Intraventricular anti-miR-155 treatment derepressed microglial miR-155 targeted genes, and peripheral anti-miR-155 treatment prolonged survival.


CONCLUSIONS
We found overexpression of miR-155 in the SOD1 mouse and in both sporadic and familial human ALS. Targeting miR-155 in SOD1 mice restores dysfunctional microglia and ameliorates disease. These findings identify miR-155 as a therapeutic target for the treatment of ALS.
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02112.
Oleg
O
Butovsky
Mark P
MP
Jedrychowski
Ron
R
Cialic
Susanne
S
Krasemann
Gopal
G
Murugaiyan
Zain
Z
Fanek
David J
DJ
Greco
Pauline M
PM
Wu
Camille E
CE
Doykan
Olga
O
Kiner
Robert J
RJ
Lawson
Matthew P
MP
Frosch
Nathalie
N
Pochet
Rachid El
RE
Fatimy
Anna M
AM
Krichevsky
Steven P
SP
Gygi
Hans
H
Lassmann
James
J
Berry
Merit E
ME
Cudkowicz
Howard L
HL
Weiner
D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001057:Apolipoproteins E / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D020320:Oligoribonucleotides, Antisense / Q000627:therapeutic use; D010587:Phagocytosis / Q000187:drug effects / Q000235:genetics; D013116:Spinal Cord / Q000473:pathology*; D013482:Superoxide Dismutase / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
D001057:Apolipoproteins E; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D020320:Oligoribonucleotides, Antisense; D016212:Transforming Growth Factor beta; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase