Kctd13の削除は,増加したRhoA経由でシナプス伝達を減少させる

Christine Ochoa Escamilla¹, Irina Filonova¹, Angela K Walker¹

¹Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8813, USA.

Nature

|November 2, 2017

まとめ

ネズミのKctd13遺伝子の削除はシナプス伝播を減少させ,神経精神疾患に関連する神経機能にKCTD13を関与させる. この研究は,Kctd13を明確にします.

科学分野:

神経科学
遺伝学
発達生物学

背景:

16p11. 2染色体領域の複製数変異は,自閉症スペクトル障害を含む神経精神疾患と関連しています.
KCTD13は神経発達のフェノタイプに関与する16p11.2領域内の遺伝子ですが,哺乳類の脳におけるその機能はよく理解されていません.

研究の目的:

哺乳類の脳における KCTD13 遺伝子の機能を研究する.
KCTD13のシナプス伝達,神経生成,脳サイズにおける役割を決定する.
KCTD13の機能の潜在的な治療的影響を探求する.

主な方法:

マウスモデルにおけるKctd13の遺伝子削除
シナプス伝送の評価
Ras ホモログ遺伝子ファミリー,メンバーA (RhoA) レベルの測定
RhoAの薬学的な阻害
マウスとゼブラフィッシュの脳サイズと神経生成の評価

主要な成果:

マウスにおけるKctd13の削除は,シナプス伝播の減少をもたらした.
シナプス伝播の減少はRhoA濃度の上昇と相関しており,RhoA抑制によって逆転した.
前回のノックダウン研究とは対照的に,Kctd13の消去はマウスやゼブラフィッシュの脳サイズまたは神経生成の増加につながらなかった.

結論:

KCTD13は,神経機能,特にシナプス伝達を調節する上で重要な役割を果たします.
RhoAシグナル伝達の増加は,KCTD13の欠失が神経機能に与える影響の鍵となるメカニズムである.
KCTD13は脳のサイズや神経形成の重要なレギュラーではありません.
RhoAは,KCTD13の削除に関連した神経精神疾患の潜在的治療標的を代表する可能性があります.

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