多発性硬化症におけるニューロンの脆弱性と多世代多様性

Lucas Schirmer^1,2,3,4, Dmitry Velmeshev^1,5, Staffan Holmqvist²

¹Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.

Nature

|July 19, 2019

まとめ

多発性硬化症 (MS) は特定の上部皮質の神経細胞を損傷し,膠質細胞を活性化します. この研究では,神経細胞の脆弱性や状神経の反応を強調して,MSの病変における細胞の変化を明らかにした.

科学分野:

神経科学
免疫学
ゲノミクス

背景:

多発性硬化症 (MS) は慢性神経炎症疾患で,再発・寛解,灰白質の明確な病変,進行性神経変性によって特徴付けられます.
MS病変の細胞と分子の変化を理解することは,疾患のメカニズムを明らかにし,治療標的を特定するために不可欠です.

研究の目的:

多発性硬化症の病変における細胞型特異のトランスクリプトミカル変異を調査する.
中枢神経系における脆弱なニューロン集団と膠質活性化パターンを特定する

主な方法:

単核RNAシーケンシング (snRNA-seq) は,MS病変の様々な細胞系における遺伝子発現変化をプロファイルするために使用されました.
マルチプレックス in situ ハイブリデーションは,主要な発見の検証に使用されました.
マウスとヒトの細胞培養における機能的測定は,ミエリン転写のマイクログリアルファゴシトーシスを確認した.

主要な成果:

上部皮質層のCUX2発現性発射神経細胞の選択的脆弱性と喪失が観察され,ストレス反応遺伝子と長い非コーディングRNAのアップレギュレーションに関連した.
ストレスを受けたオリゴデンドロサイト,反応性のあるアストロサイト,および活性化されたマイクログリアのシグネチャーは,主に病変の縁で発見された.
snRNA-seqは,ミエリントランスクリプトを摂取するファゴサイト化マイクログリア/マクロファージを特定し,さらに機能分析で検証した.

結論:

MSの病変は系統と地域特有の転写学的変化を示し,皮質の神経損傷と分別のある膠質活性化パターンを表します.
皮質ニューロンの脆弱性と膠質反応は多発性硬化病変の進行に寄与する.

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