Mendeley出力
＜学術雑誌論文＞
神経難病の謎を紐解く分子を求めて
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| 概要 | 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.続きを見る |
| 目次 | はじめに 1．中枢神経脱髄疾患の鍵となる分子の発見と神経・軸索変性への展開 2．末梢神経脱髄疾患の鍵となる分子の発見 3．神経障害性疼痛の鍵となる分子の発見と自己抗体介在性神経障害性疼痛 おわりに |
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| 登録日 | 2021.01.05 |
| 更新日 | 2021.03.03 |