Connexin astrocytopathy and novel therapeutic strategy targeting connexin hemichannels in demyelinating disease

2013 Fiscal Year Final Research Report

• Project/Area Number: 24790889
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurology
• Research Institution: Kyushu University
• Principal Investigator: MASAKI Katsuhisa 九州大学, 医学(系)研究科(研究院), 助教 (90612903)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Keywords: コネキシン / 多発性硬化症 / 視神経脊髄炎 / Balo病

Research Abstract

To investigate the relationship between astrocytopathy and demyelination, we examined the expression of connexins (Cx). We evaluated the expressions of astrocytic Cx43/Cx30 and oligodendrocytic Cx47/Cx32 among autopsied cases with demyelinating disorders. In Balo disease (BD), Cx43, Cx32 and Cx47 were extensively diminished. In the leading edge area, Cx43 and AQP4 loss preceded Cx47 loss. Three cases with multiple sclerosis (MS) and six with neuromyelitis optica (NMO) showed preferential Cx43 and AQP4 loss far beyond the demyelinated areas, while vasculocentric deposition of immunoglobulins or complements was observed in four of the six NMO cases. Some NMO cases showed preferential myelin-associated glycoprotein (MAG) loss. Our findings indicate that disruption of Cx gap junction and preferential MAG loss could occur in MS, BD and NMO, and could be a common denominator. Inhibition of Cx hemichannels is a possible therapeutic target for demyelinating disorders.

Research Products

• [Journal Article] South Japan Multiple Sclerosis Genetics Consortium. Distinct genetic and infectious profiles in Japanese neuromyelitis optica patients according to anti-aquaporin 4 antibody status (2013)
  • Author(s): Yoshimura S, Isobe N, Matsushita T, Yonekawa T, Masaki K, Sato S, Kawano Y, Kira J
  • Journal Title: J Neurol Neurosurg Psychiatry Volume: 84 Pages: 29-34
• [Journal Article] Clinical relevance of serum aquaporin-4 antibody levels in neuromyelitis optica (2013)
  • Author(s): Isobe N, Yonekawa T, Matsushita T, MasakiK, Yoshimura S, Fichna J, Chen S, Furmaniak J, Smith BR, Kira J
  • Journal Title: Neurochem Res Volume: 38 Pages: 997-1001
• [Journal Article] Connexin 43 astrocytopathy linked to rapidly progressive multiple sclerosis and neuromyelitis optica (2013)
  • Author(s): Masaki K, Suzuki SO, Matsushita T, Matsuoka T, Imamura S, Yamasaki R, Suzuki M, Suenaga T, Iwaki T, Kira J
  • Journal Title: PLoS One Volume: 8 Pages: e72919
• [Journal Article] An autopsy case of Marburg variant of multiple sclerosis (acute multiple sclerosis) (2013)
  • Author(s): Suzuki M, Kawasaki H, Masaki K, Suzuki SO, Terada T, Tsuchida T, Tokuyama T, Kono S, Komori T, Baba S, Kira J, Miyajima H
  • Journal Title: Intern Med Volume: 52 Pages: 1825-32
• [Journal Article] A nationwide survey of hypertrophic pachymeningitis in Japan (2013)
  • Author(s): Yonekawa T, Murai H, Utsuki S, Matsushita T, Masaki K, Isobe N, Yamasaki R, Yoshida M, Kusunoki S, Sakata K, Fujii K, Kira J
  • Journal Title: J Neurol Neurosurg Psychiatry
  • DOI: 10.1136/jnnp-2013-306410.
• [Journal Article] Comparison of clinical, immunological and neuroimaging features between anti-aquaporin-4 antibody-positive and –negative Sjögren's syndrome patients with central nervous system manifestations (2012)
  • Author(s): Riwanti Estiasari, Matsushita T, Masaki K, Akiyama T, Yonekawa T, Isobe N, Kira J
  • Journal Title: Mult Scler Volume: 18 Pages: 807-816
• [Journal Article] Quantitative assays for anti-aquaporin-4 antibody with subclass analysis in neuromyelitis optica (2012)
  • Author(s): Isobe N, Yonekawa T, Matsushita T, Kawano Y, Masaki K, Yoshimura S, Fichna J, Chen S, Furmaniak J, Smith BR, Kira J
  • Journal Title: Mult Scler Volume: 18 Pages: 1541-1551
• [Journal Article] Extensive loss of connexins in Baló's disease : evidence for an auto- antibodyindependent astrocytopathy via impaired astrocyte-oligodendrocyte/myelin interaction (2012)
  • Author(s): Masaki K, Suzuki SO, Matsushita T, Yonekawa T, Matsuoka T, Isobe N, Motomura K, Wu XM, Tabira T, Iwaki T, Kira J
  • Journal Title: Acta Neuropathol Volume: 123 Pages: 887-900
• [Journal Article] Clinical disability progression and platelet GP IIb/IIIa values in patients with atopic myelitis (2012)
  • Author(s): Gulibahaer A, Yamashita K, Torii T , Furuta K, Isobe N, Matsushita T, Masaki K, Matsumoto S, Kira J
  • Journal Title: J Neuroimmunol Volume: 246 Pages: 108-112
• [Journal Article] HLA-DPB1* 0201 is associated with susceptibility to atopic myelitis in Japanese (2012)
  • Author(s): Sato S, Isobe N, Yoshimura S, Kanamori Y, Masaki K, Matsushita T, Kira J
  • Journal Title: J Neuroimmunol Volume: 251 Pages: 110-113
• [Journal Article] South Japan MultipleSclerosis Genetics Consortium. Genetic and infectious profiles of Japanese multiple sclerosis patients (2012)
  • Author(s): Yoshimura S, Isobe N, Yonekawa T, Matsushita T, Masaki K, Sato S, Kawano Y, Yamamoto K, Kira J
  • Journal Title: PLoS One Volume: 7(11) Pages: e48592
• [Presentation] 脱髄性疾患におけるConnexin 43 脱落は病態の急速な進行およびdistal oligodendrogliopathy型脱髄と関連する (2013)
  • Author(s): 眞﨑勝久、鈴木諭、松下拓也、松岡健、鈴木万幾子、末長敏彦、岩城徹、吉良潤一
  • Organizer: 第25回日本神経免疫学会学術集会
  • Place of Presentation: 下関
  • Year and Date: 20131127-29
• [Presentation] Rapidly progressive MS and gliopathy (2013)
  • Author(s): Masaki K
  • Organizer: PACTRIMS
  • Place of Presentation: Kyoto
  • Year and Date: 20131106-08
• [Presentation] Connexin gap junction pathology in the SOD1 transgenic mouse model of amyotrophic lateral sclerosis (ALS) (2013)
  • Author(s): Masaki K, Cui YW, Yamasaki R, Hayashi S, Nagara S, Kawamura MF, Sato S, Ohyagi Y, Kira J
  • Organizer: Neuro2013
  • Place of Presentation: Kyoto
  • Year and Date: 20130620-23
• [Presentation] Distal oligodendrogliopathy 型脱髄におけるコネキシンアストロサイトパチーの関与 (2013)
  • Author(s): 眞﨑勝久、鈴木諭、松下拓也、松岡健、鈴木万幾子、末長敏彦、岩城徹、吉良潤一
  • Organizer: 第54回日本神経学会学術大会
  • Place of Presentation: 東京(口演)
  • Year and Date: 20130529-0601
• [Presentation] Early disruption of astrocytic connexins in multiple sclerosis, Baló's disease and neuromyelitis optica (2012)
  • Author(s): Masaki K、Suzuki SO、Matsushita T、Matsuoka T、Suzuki M、Suenaga T、Tabira T、Iwaki T、Kira J
  • Organizer: ECTRIMS
  • Place of Presentation: Lyon
  • Year and Date: 20121010-13
• [Presentation] Connexin astrocytopathy in multiple sclerosis, Baló's disease and neuromyelitis optica (2012)
  • Author(s): Masaki K、Suzuki SO、Matsushita T、Matsuoka T、Suenaga T、Tabira T、Iwaki T、Kira J
  • Organizer: American Neurological Association 2012 Annual Meeting
  • Place of Presentation: Boston
  • Year and Date: 20121007-09
• [Presentation] 脱髄性疾患における広汎なコネキシン脱落と病態への関与 (2012)
  • Author(s): 眞﨑勝久、鈴木諭、松下拓也、松岡健、鈴木万幾子、 末長敏彦、田平武、岩城徹、吉良潤一
  • Organizer: 第24回日本神経免疫学会学術集会
  • Place of Presentation: 長野
  • Year and Date: 20120920-21
• [Presentation] Molecular pathology of astrocytopathy in Baló's disease and tumefactive MS (2012)
  • Author(s): Masaki K、Kira J
  • Organizer: 第35回日本神経科学大会
  • Place of Presentation: 名古屋
  • Year and Date: 20120918-21
• [Presentation] Molecular pathology of astrocytopathy in Baló's disease and tumefactive MS (2012)
  • Author(s): Masaki K、Kira J
  • Organizer: PACTRIMS
  • Place of Presentation: 北京
  • Year and Date: 20120913-15
• [Presentation] 多発性硬化症、視神経脊髄炎、Baló 病における広汎なコネキシン蛋白の脱落と病態への関与 (2012)
  • Author(s): 眞﨑勝久、鈴木諭、松下拓也、松岡健、米川智、磯部紀子、田平武、岩城徹、吉良潤一
  • Organizer: 第53回日本神経学会学術大会
  • Place of Presentation: 東京(口演)
  • Year and Date: 20120522-25
• [Book] 神経病理.アクチュアル脳・神経疾患の臨床.最新アプローチ多発性硬化症と視神経脊髄炎.辻省次(総編集).吉良潤一(専門編集). (2012)
  • Author(s): 真崎勝久、吉良潤一
  • Total Pages: 29-36
  • Publisher: 中山書店
• [Book] 多発性硬化症の類縁疾患バロー病.アクチュアル脳・神経疾患の臨床.最新アプローチ多発性硬化症と視神経脊髄炎.辻省次(総編集).吉良潤一(専門編集). (2012)
  • Author(s): 真崎勝久、吉良潤一
  • Total Pages: 99-103
  • Publisher: 中山書店
• [Book] OSMS におけるAQP4の病態意義. 神経内科 76 (2012)
  • Author(s): 真崎勝久, 吉良潤一
  • Total Pages: 537-542
• [Book] Balo病における広汎なコネキシン蛋白の脱落. MS frontier 1: 3 (2012)
  • Author(s): 真崎勝久
  • Total Pages: 1-33
• [Book] アストロサイトパチーと脳細胞間情報伝達機構の修復戦略. 臨床神経 52 (2012)
  • Author(s): 真崎勝久
  • Total Pages: 1354-6
• [Remarks]
  • URL: http://www.med.kyushu-u.ac.jp/neuro/