Therapy development for neuromuscular degeneration in motor neuron diseases

• Project/Area Number: 26293206
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Nagoya University
• Principal Investigator: KATSUNO Masahisa 名古屋大学, 医学(系)研究科(研究院), 教授 (50402566)
• Co-Investigator(Kenkyū-buntansha): 祖父江 元 名古屋大学, 医学(系)研究科(研究院), 特任教授 (20148315) ; 近藤 直英 名古屋大学, 医学部附属病院, 医員 (20725527) ; 佐橋 健太郎 名古屋大学, 医学部附属病院, 医員 (90710103)
• Co-Investigator(Renkei-kenkyūsha): OKADA Yohei 愛知医科大学, 医学部, 特任准教授 (30383714)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,510,000 (Direct Cost: ¥12,700,000、Indirect Cost: ¥3,810,000); Fiscal Year 2016: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2015: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
• Keywords: 運動ニューロン / 骨格筋 / エピジェネティクス / ミトコンドリア / NFkB / 球脊髄性筋萎縮症 / 筋萎縮性側索硬化症 / Aktシグナル / DNAメチル化 / 脳神経疾患 / 神経科学 / シグナル伝達 / プロテオーム / 神経変性疾患 / リン酸化 / シグナル

Outline of Final Research Achievements

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.

Research Products

• [Journal Article] Correlation of insulin resistance and motor function in spinal and bulbar muscular atrophy. (2017)
  • Author(s): Nakatsuji H, Araki A, Hashizume A, Hijikata Y, Yamada S, Inagaki T, Suzuki K, Banno H, Suga N, Okada Y, Ohyama M, Nakagawa T, Kishida K, Funahashi T, Shimomura I, Okano H, Katsuno M, Sobue G.
  • Journal Title: J Neurol. Volume: in press Issue: 5 Pages: 839-847
  • DOI: 10.1007/s00415-017-8405-3
  • NAID: 120006331845
  • Peer Reviewed / Open Access
• [Journal Article] Decreased Peak Expiratory Flow Associated with Muscle Fiber-Type Switching in Spinal and Bulbar Muscular Atrophy. (2016)
  • Author(s): Yamada S, Hashizume A, Hijikata Y, Inagaki T, Suzuki K, Kondo N, Kawai K, Noda S, Nakanishi H, Banno H, Hirakawa A, Koike H, Halievski K, Jordan CL, Katsuno M, Sobue G.
  • Journal Title: PLoS One. Volume: 11(12) Issue: 12 Pages: e0168846-e0168846
  • DOI: 10.1371/journal.pone.0168846
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] FUS/TLS acts as an aggregation-dependent modifier of polyglutamine disease model mice. (2016)
  • Author(s): Kino Y, Washizu C, Kurosawa M, Yamada M, Doi H, Takumi T, Adachi H, Katsuno M, Sobue G, Hicks GG, Hattori N, Shimogori T, Nukina N.
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 35236-35236
  • DOI: 10.1038/srep35236
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Exosome secretion is a key pathway for clearance of pathological TDP-43. (2016)
  • Author(s): Iguchi Y,, Eid L,, Parent M,, Soucy G,, Bareil C,, Riku Y,, Kawai K,, Takagi S,, Yoshida M,, Katsuno M,, Sobue G., Julien JP.
  • Journal Title: Brain Volume: 139 Issue: 12 Pages: 3187-3201
  • DOI: 10.1093/brain/aww237
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Impaired muscle uptake of creatine in spinal and bulbar muscular atrophy. (2016)
  • Author(s): Hijikata Y., Katsuno M., Suzuki K., Hashizume A., Araki A., Yamada S., Inagaki T., Iida M., Noda S., Nakanishi H., Banno H., Mano T., Hirakawa A., Adachi H., Watanabe H., Yamamoto M., Sobue G.
  • Journal Title: Ann Clin Transl Neurol Volume: 3 Issue: 7 Pages: 537-546
  • DOI: 10.1002/acn3.324
  • Peer Reviewed / Open Access
• [Journal Article] Silencing neuronal mutant androgen receptor in a mouse model of spinal and bulbar muscular atrophy. (2015)
  • Author(s): Sahashi K, Katsuno M, Hung G, Adachi H, Kondo N, Nakatsuji H, Tohnai G, Iida M, Bennett CF, Sobue G.
  • Journal Title: Hum Mol Genet. Volume: 24(21) Issue: 21 Pages: 5985-94
  • DOI: 10.1093/hmg/ddv300
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] FUS regulates AMPA receptor function and FTLD/ALS-associated behaviour via GluA1 mRNA stabilization. (2015)
  • Author(s): Udagawa, T., Fujioka, Y., Tanaka, M., Honda, D., Yokoi, S., Riku, Y., Ibi, D., Nagai, T., Yamada, K., Watanabe, H., Katsuno, M., Inada, T., Ohno, K., Sokabe, M., Okado, H., Ishigaki S*., and Sobue, G.
  • Journal Title: Nat Commun Volume: 6 Issue: 1 Pages: 7098-7098
  • DOI: 10.1038/ncomms8098
  • Peer Reviewed / Open Access
• [Journal Article] Astrocyte-Derived TGF-β1 Accelerates Disease Progression in ALS Mice by Interfering with the Neuroprotective Functions of Microglia and T Cells. (2015)
  • Author(s): Endo F, Komine O, Fujimori-Tonou N, Katsuno M, Jin S, Watanabe S, Sobue G, Dezawa M, Wyss-Coray T, Yamanaka K
  • Journal Title: Cell Reports Volume: 11 Issue: 4 Pages: 592-604
  • DOI: 10.1016/j.celrep.2015.03.053
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Pioglitazone suppresses neuronal and muscular degeneration caused by polyglutamine-expanded androgen receptors. (2015)
  • Author(s): Iida M, Katsuno M, Nakatsuji H, Adachi H, Kondo N, Miyazaki Y, Tohnai G, Ikenaka K, Watanabe H, Yamamoto M, Kishida K, Sobue G
  • Journal Title: Hum Mol Genet. Volume: 24 Issue: 2 Pages: 314-329
  • DOI: 10.1093/hmg/ddu445
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Paeoniflorin eliminates a mutant AR via NF-YA-dependent proteolysis in spinal and bulbar muscular atrophy. (2014)
  • Author(s): Tohnai G, Adachi H, Katsuno M, Doi H, Matsumoto S, Kondo N, Miyazaki Y, Iida M, Nakatsuji H, Qiang Q, Ding Y, Watanabe H, Yamamoto M, Ohtsuka K, Sobue G.
  • Journal Title: Hum Mol Genet. Volume: 23 Issue: 13 Pages: 3552-3565
  • DOI: 10.1093/hmg/ddu066
  • Peer Reviewed / Open Access
• [Journal Article] Lower motor neuron involvement in TAR DNA-binding protein of 43 kDa-related frontotemporal lobar degeneration and amyotrophic lateral sclerosis. (2014)
  • Author(s): Riku Y, Watanabe H, Yoshida M, Tatsumi S, Mimuro M, Iwasaki Y, Katsuno M, Iguchi Y, Masuda M, Senda J, Ishigaki S, Udagawa T, Sobue G
  • Journal Title: JAMA Neurol. Volume: 71 Issue: 2 Pages: 172-179
  • DOI: 10.1001/jamaneurol.2013.5489
  • Peer Reviewed
• [Journal Article] Brugada syndrome in spinal and bulbar muscular atrophy. (2014)
  • Author(s): Araki A, Katsuno M, Suzuki K, Banno H, Suga N, Hashizume A, Mano T, Hijikata Y, Nakatsuji H, Watanabe H, Yamamoto M, Makiyama T, Ohno S, Fukuyama M, Morimoto S, Horie M, Sobue G
  • Journal Title: Neurology Volume: 82 Issue: 20 Pages: 1813-1821
  • DOI: 10.1212/wnl.0000000000000434
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Anti-androgen flutamide protects male mice from androgen-dependent toxicity in three models of spinal bulbar muscular atrophy (2014)
  • Author(s): Renier KJ, Troxell-Smith SM, Johansen JA, Katsuno M, Adachi H, Sobue G, Chua JP, Sun Kim H, Lieberman AP, Breedlove SM, Jordan CL
  • Journal Title: Endocrinology. Volume: 155 Issue: 7 Pages: 2624-2634
  • DOI: 10.1210/en.2013-1756
  • Peer Reviewed
• [Journal Article] Schwann cell involvement in the peripheral neuropathy of spinocerebellar ataxia type 3. (2014)
  • Author(s): Suga N, Katsuno M, Koike H, Banno H, Suzuki K, Hashizume A, Mano T, Iijima M, Kawagashira Y, Hirayama M, Nakamura T, Watanabe H, Tanaka F, Sobue G
  • Journal Title: Neuropathol Appl Neurobiol. Volume: 40 Issue: 5 Pages: 628-639
  • DOI: 10.1111/nan.12055
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 神経変性疾患モデルにおけるタクロリムスとその誘導体の治療効果 (2016)
  • Author(s): 藤内玄規, 勝野雅央, 足立弘明, 佐橋健太郎, 近藤直英, 中辻秀朗, 飯田円, 祖父江元
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(神奈川県 横浜市)
  • Year and Date: 2016-11-30
• [Presentation] Dysregulated Akt signaling pathway in spinal and bulbar muscular atrophy (SBMA) (2016)
  • Author(s): 飯田円，勝野雅央，佐橋健太郎，中辻秀朗，近藤直英，藤内玄規，祖父江元
  • Organizer: 第39回日本神経科学大会
  • Place of Presentation: パシフィコ横浜(神奈川県 横浜市)
  • Year and Date: 2016-07-20
• [Presentation] Potential therapeutic targets in polyglutamine-mediated diseases. (2016)
  • Author(s): Katsuno M.
  • Organizer: 1st International Asidan Symposium on Asida River/Japan
  • Place of Presentation: ホテル鴎風亭(広島県福山市)
  • Year and Date: 2016-07-01
  • Int'l Joint Research / Invited
• [Presentation] Dissection of mechanisms of neuronal degeneration in polyglutamine disease. (2016)
  • Author(s): 佐橋健太郎, 近藤直英, 中辻秀朗, 藤内玄規, 飯田円, 勝野雅央, 祖父江元
  • Organizer: 第57回日本神経学会学術大会
  • Place of Presentation: 神戸コンベンションセンター(兵庫県 神戸市)
  • Year and Date: 2016-05-18
• [Presentation] The effect of exercise in a mouse model of spinal and bulbar muscular atrophy. (2016)
  • Author(s): 中辻秀朗, 勝野雅央, 近藤直英, 藤内玄規, 佐橋健太郎, 飯田円, 祖父江元
  • Organizer: 第57回日本神経学会学術大会
  • Place of Presentation: 神戸コンベンションセンター(兵庫県 神戸市)
  • Year and Date: 2016-05-18
• [Presentation] Dysregulated Akt signaling pathway in spinal and bulbar muscular atrophy (SBMA). (2016)
  • Author(s): 飯田円，勝野雅央，佐橋健太郎，中辻秀朗，近藤直英，藤内玄規，祖父江元
  • Organizer: 第57回日本神経学会学術大会
  • Place of Presentation: 神戸コンベンションセンター(兵庫県 神戸市)
  • Year and Date: 2016-05-18
• [Presentation] Application of biomarkers for early-stage of spinal and bulbar muscular atrophy to clincal trials (2016)
  • Author(s): 勝野雅央
  • Organizer: 第57回日本神経学会学術大会
  • Place of Presentation: 神戸コンベンションセンター(兵庫県 神戸市)
  • Year and Date: 2016-05-18
  • Invited
• [Presentation] トランスレーショナルリサーチ入門:研究が実用になるまで. (2016)
  • Author(s): 勝野雅央
  • Organizer: 第4回ヤング・サイエンティスト・シンポジウム
  • Place of Presentation: パシフィコ横浜(神奈川県 横浜市)
  • Invited
• [Presentation] Cell cycle inhibitor ameliorates motor neuron degeneration induced by polyglutamine-expanded androgen receptor. (2015)
  • Author(s): Katsuno M, Adachi H, Sahashi K, Kondo N, Iida M, Nakatsuji H, Tohnai G, Sobue G.
  • Organizer: The 26th International Symposium on ALS/MND
  • Place of Presentation: Orland, USA
  • Year and Date: 2015-12-11
  • Int'l Joint Research
• [Presentation] Disruped muscle uptake of creatine in spinal and bulbar muscular atrophy. (2015)
  • Author(s): Hijikata Y, Katsuno M, Hashizume A, Yamada S, Inagaki T, Suzuki K, Banno H, Sobue G.
  • Organizer: The 26th International Symposium on ALS/MND
  • Place of Presentation: Orland, USA
  • Year and Date: 2015-12-11
  • Int'l Joint Research
• [Presentation] Antisense inhibition of neuronal androgen receptor in spinal and bulbar muscular atrophy. (2015)
  • Author(s): Sahashi K, Katsuno M, Hung G, Adachi H, Kondo N, Nakatsuji H, Tohnai G, Iida M, Bennett CF, Sobue G
  • Organizer: 第33回日本神経治療学会総会
  • Place of Presentation: 名古屋国際会議場(愛知県名古屋市)
  • Year and Date: 2015-11-26
• [Presentation] 球脊髄性筋萎縮症モデルにおけるタクロリムス誘導体の治療効果 (2015)
  • Author(s): 藤内玄規, 足立弘明, 勝野雅央, 佐橋健太郎, 近藤直英, 中辻秀朗, 飯田円, 祖父江 元.
  • Organizer: 第33回日本神経治療学会総会
  • Place of Presentation: 名古屋国際会議場(愛知県名古屋市)
  • Year and Date: 2015-11-26
• [Presentation] Dysregulated nuclear factor-κB (NFκB) signaling in spinal and bulbar muscular atrophy (SBMA). (2015)
  • Author(s): Iida M, Katsuno M, Nakatsuji H, Adachi H, Kondo N, Tohnai G, Sobue G.
  • Organizer: 第38回日本神経科学大会
  • Place of Presentation: 神戸国際会議場(兵庫県神戸市)
  • Year and Date: 2015-07-26
• [Presentation] 運動ニューロン疾患の分子病態解明に基づく治療標的開発. (2015)
  • Author(s): 勝野雅央.
  • Organizer: 第56回日本神経学会学術大会
  • Place of Presentation: 朱鷺メッセ(新潟県新潟市)
  • Year and Date: 2015-05-20
  • Invited
• [Presentation] Expression and role of TFEB in spinal and bulbar muscular atrophy (2015)
  • Author(s): 藤内 玄規, 足立 弘明, 勝野 雅央, 近藤 直英, 宮崎 雄, 飯田 円, 中辻 秀朗, 丁 瑩, 渡辺 宏久, 祖父江 元.
  • Organizer: 第56回日本神経学会学術大会
  • Place of Presentation: 朱鷺メッセ(新潟県新潟市)
  • Year and Date: 2015-05-20
• [Presentation] Intracerebroventricular administration of antisense oligonucleotides improves disease phenotypes in SBMA mice. (2015)
  • Author(s): Sahashi K, Katsuno M, Hung G, Adachi H, Kondo N, Nakatsuji H, Tohnai G, Iida M, Bennett CF, Sobue G.
  • Organizer: 第56回日本神経学会学術大会
  • Place of Presentation: 朱鷺メッセ(新潟県新潟市)
  • Year and Date: 2015-05-20
• [Presentation] The effects of pioglitazone on spinal and bulbar muscular atrophy. (2015)
  • Author(s): Iida M, Katsuno M, Nakatsuji H, Adachi H, Kondo N, Miyazaki Y, Tohnai G, Watanabe H, Yamamoto M, Kishida K, Sobue G.
  • Organizer: 第56回日本神経学会学術大会
  • Place of Presentation: 朱鷺メッセ(新潟県新潟市)
  • Year and Date: 2015-05-20
• [Presentation] The involvement of glial cells in FUS-related ALS/FTLD pathophysiology -FUS knock-down glial cells have a neuro-protective effect. (2014)
  • Author(s): Fujioka Y, Ishigaki S, Shiromizu T,, Udagawa T, Honda D, Yokoi S, Ikenaka K, Katsuno M, Tomonaga T, Sobue G
  • Organizer: Neuroscience 2014
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] Androgen-dependent deficits in muscle-derived BDNF correlate with motor dysfunction in two mouse models of spinal bulbar muscular atrophy. (2014)
  • Author(s): Halievski K, Xu Y, Henley CL, Katsuno M, Adachi H, Sobue G, Breedlove S, Jordan CL
  • Organizer: Neuroscience 2014
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] SBMA motor dysfunction may be due to failed neuromuscular transmission. (2014)
  • Author(s): Xu, Atchison W, Adachi H, Katsuno M, Sobue G, Breedlove S, Jordan CL
  • Organizer: Neuroscience 2014
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] The blood-spinal cord barrier is temporarily impaired in TDP-43 conditional knockout mice. (2014)
  • Author(s): Sasaki S, Iguchi Y, Katsuno M, Sobue G.
  • Organizer: The 13th International Congress on Neuromuscular Diseases.
  • Place of Presentation: Nice, France
  • Year and Date: 2014-07-05 – 2014-07-10