神経難病の謎を紐解く分子を求めて

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吉良潤一，糸山泰人，田平武，柴崎浩，黒岩義五郎：日本人多発性硬化症患者の自然経過とステロイド治療に

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（特に重要な文献については，番号をゴシック体で表記している．）

著者プロフィール

吉良 潤一（きら じゅんいち）

国際医療福祉大学教授（大学院医学研究科トランスレーショナルニューロサイエンスセンター・福岡

薬学部）

．福岡中央病院脳神経センター長．医学博士．

◆略歴 1954 年大分県佐伯市に生まれる．1979 年九州大学医学部医学科卒業．1982 年米国国立衛

生研究所 visiting fellow．1985 年九州大学医学部附属病院助手．1991 年九州大学医学部附

属病院講師．1995 年九州大学医学部神経内科助教授．1997 年九州大学医学部神経内科教

授．2000 年九州大学大学院医学研究院神経内科学分野教授．2020 年より現職．

◆研究テーマと抱負 難治性神経疾患の分子メカニズムの解明と治療開発．特に多発性硬化症や慢

性炎症性脱髄性多発神経炎などの神経免疫疾患を対象としている．臨床の現場での診察に

基づいた気づきから分子レベルの病態解明をめざしている．新しい病気を発見すること，

新しい病因を解明すること，新しい治療法を開発することが，今でも夢です．

112

Key Molecules to Decipher the Mechanisms of

Intractable Neurological Diseases

Jun-ichi KIRA

Translational Neuroscience Center, Graduate School of Medicine and School of

Pharmacy at Fukuoka, International University of Health and Welfare

Department of Neurology, Brain and Nerve Center, Fukuoka Central Hospital

Professor Emeritus, Kyushu University

Abstract

Intractable neurological diseases encompass neuroimmunological and neurodegenerative diseases.

Recently, many disease-modifying drugs that significantly decrease acute exacerbations have been

used in clinical practice for neuroimmunological diseases such as multiple sclerosis (MS) ; however,

none have been reported to ameliorate progressive disease. Since its establishment in 1963, the

Department of Neurology at Kyushu University has focused on deciphering the mechanisms of

intractable neurological diseases. Recently, key molecules with critical roles in disease cascades of

intractable neurological diseases have been discovered. We used molecular immunopathology of

autopsied materials to identify marked alterations in glial connexins (Cxs) in acute and chronic

demyelinating lesions of MS as well as neuromyelitis optica (NMO) and Balóʼs concentric sclerosis.

Similar changes were also observed in acute and chronic experimental autoimmune encephalomyelitis

(EAE), an animal model of MS. Glial Cxs form gap junction (GJ) channels, which connect glial cells

constituting the glial syncytium. The glial syncytium is critical for maintaining brain homeostasis by

supplying energy and buffering potassium ions via Cx GJ channels. We established oligodendroglial

Cx47-inducible conditional knockout (Cx47 icKO) mice and induced EAE by immunization with myelin

oligodendrocyte glycoprotein. Cx47 icKO mice showed a marked exacerbation of acute and chronic

EAE with progressive demyelination. Microarray and immunohistochemistry demonstrated Cx47

icKO mice had markedly increased numbers of proinflammatory A1 astrocytes and proinflammatory

and injury-responsive microglia producing inflammatory chemokines, which attracted T-helper 17

cells that potentiated autoimmune demyelination. By contrast, astroglial Cx30 KO mice had attenuated

chronic EAE with preserved myelin and axons. These findings suggest a novel role for glial Cxs in

regulating brain inflammation in addition to metabolic functions that maintain brain homeostasis. Our

large scale genome-wide association studies identified a single nucleotide polymorphism in potassium

calcium-activated channel subfamily M alpha 1 (KCNMA1), which can reduce its expression in cells,

was the largest genetic risk for severe disability caused by transverse myelitis in NMO. KCNMA1

expression in NMO lesions was markedly diminished. KCNMA1 in astrocyte endfeet is critical for

potassium ion buffering mediated by the glial syncytium by discharging potassium ions to blood

vessels. Therefore, the decreased expression of KCNMA1 may disturb axonal functions by impairing

potassium buffering necessary for repeatable axonal excitability in NMO. The exploration of

autoantibodies against neural tissues revealed that neurofascin 155 (NF155) in the nodes of Ranvier is a

target antigen in combined central and peripheral demyelination (CCPD) /chronic inflammatory

demyelinating polyneuropathy (CIDP). This finding has contributed to the establishment of the novel

concept of autoimmune nodopathy. We also found that plexin D1, expressed by pain-conducting small

dorsal ganglion neurons, is a target antigen in neuropathic pain. Intrathecally-administered anti-plexin

D1 antibody successfully reproduced mechanical and thermal allodynia in experimental animals,

suggesting this antibody is pathogenic. These observations have contributed to the establishment of

the disease concept of autoantibody-mediated neuropathic pain, which can be treated by

immunotherapy. Through further pathological, immunological, and genetic studies, key molecules in

intractable neurological diseases will be discovered and enable us to reclassify intractable neurological

diseases based on their molecular pathomechanisms and hopefully eradicate intractable neurological

diseases in the future.

Key Words : demyelinating disease, neuropathic pain, connexin, neurofascin 155, plexin D1

...