Research Project
Grant-in-Aid for Scientific Research (B)
We exploited antisense oligonucleotides (ASOs) to inhibit mutant androgen receptor (AR) RNA levels in the central nervous system and explored its therapeutic effects in the model mouse of spinal and bulbar muscular atrophy (SBMA) that harbors mutant AR gene with 97 CAGs. Intracerebroventricular ASO administration in the SBMA mice efficiently suppressed the mutant gene expression in the central nervous system, highlighting the neurotoxicity of mutant AR in motor neurons. RG108, an inhibitor of DNA methylation suppressed motor neuron degeneration in the SBMA mouse, suggesting that the mutant AR-induced hypermethylation of DNA is implicated in the pathomechanism of SBMA. Both motor neurons and skeletal muscles of the SBMA mouse showed mitochondrial dysfunction, up-regulation of oxidative stress, and activation of NFkB signaling, all of which were mitigated by a PPARgamma agonist pioglitazone, suggesting common molecular pathways in the neuro-muscular degeneration in SBMA.
All 2017 2016 2015 2014
All Journal Article (14 results) (of which Int'l Joint Research: 4 results, Peer Reviewed: 14 results, Open Access: 9 results, Acknowledgement Compliant: 7 results) Presentation (21 results) (of which Int'l Joint Research: 3 results, Invited: 4 results)
J Neurol.
Volume: in press Issue: 5 Pages: 839-847
10.1007/s00415-017-8405-3
120006331845
PLoS One.
Volume: 11(12) Issue: 12 Pages: e0168846-e0168846
10.1371/journal.pone.0168846
Sci Rep.
Volume: 6 Issue: 1 Pages: 35236-35236
10.1038/srep35236
Brain
Volume: 139 Issue: 12 Pages: 3187-3201
10.1093/brain/aww237
Ann Clin Transl Neurol
Volume: 3 Issue: 7 Pages: 537-546
10.1002/acn3.324
Hum Mol Genet.
Volume: 24(21) Issue: 21 Pages: 5985-94
10.1093/hmg/ddv300
Nat Commun
Volume: 6 Issue: 1 Pages: 7098-7098
10.1038/ncomms8098
Cell Reports
Volume: 11 Issue: 4 Pages: 592-604
10.1016/j.celrep.2015.03.053
Volume: 24 Issue: 2 Pages: 314-329
10.1093/hmg/ddu445
Volume: 23 Issue: 13 Pages: 3552-3565
10.1093/hmg/ddu066
JAMA Neurol.
Volume: 71 Issue: 2 Pages: 172-179
10.1001/jamaneurol.2013.5489
Neurology
Volume: 82 Issue: 20 Pages: 1813-1821
10.1212/wnl.0000000000000434
Endocrinology.
Volume: 155 Issue: 7 Pages: 2624-2634
10.1210/en.2013-1756
Neuropathol Appl Neurobiol.
Volume: 40 Issue: 5 Pages: 628-639
10.1111/nan.12055