多系統萎縮症の病態機序―α-synuclein トランスジェニックマウス

Mouse model of multiple system atrophy (MSA) : Transgenic mice overexpressing α-synuclein in oligodendrocytes

多系統萎縮症（MSA）では，中枢神経系の白質のオリゴデンドロサイトでα-synucleinが異常な凝集を起こし，glial cytoplasmic inclusion（GCI）を形成する。GCIがMSAの神経変性に関与する機序は不明である。GCIの病的役割を解明するために，2',3'-cyclic nucleotide 3'-phosphodiesterase（CNP）プロモーター制御下にヒトα-synuclein遺伝子を置き，オリゴデンドロサイトにα-synucleinを強制発現させるトランスジェニック（TG）マウスを作製した。TGマウスの脳ではオリゴデンドロサイトにGCIを認め，MSAの病理と高い類似性を示し，さらに脳萎縮，神経細胞の脱落および緩徐進行性の運動障害等により，神経細胞の変性を認めた。誘導された神経変性の標的の中心は神経終末で，マウス内因性α-synucleinの蓄積が神経変性に深く関与した。

Multiple system atrophy（MSA）is a neurodegenerative disease that affects oligodendrocytes and neurons in the human central nervous system（CNS）. MSA is a sporadic synucleinopathy characterized by abnormal accumulations of filamentous α-synuclein inclusions in the CNS. These α-synuclein inclusions are most prominent in oligodendrocytes where they are known as glial cytoplasmic inclusions（GCIs）, and GCIs are diagnostic of MSA. Mechanisms of neurodegeneration in MSA are unclear. To elucidate a pathological role of GCIs in MSA neurodegeneation, transgenic（Tg）mice overexpressing human wild-type α-synuclein in oligodendrocytes under the control of the 2',3'-cyclic nucleotide 3'-phosphodiesterase（CNP）promoter were generated. The Tg mice recapitulated features of MSA including the accumulation of filamentous human α-synuclein aggregates in oligodendrocytes linked to their degeneration. Moreover, neuronal loss and slowly progressive motor impairments were also shown in the Tg mice, and endogenous mouse α-synuclein was accumulated in degenerating axons and axon terminals. The studies demonstrate that overexpression of α-synuclein in oligodendrocytes of mice results in MSA-like degeneration in the CNS and that α-synuclein inclusions in oligodendrocytes participate in the degeneration of neurons in MSA.