TDP-43とRNAは,再生する筋肉でアミロイドのようなミオ粒子を形成する

Thomas O Vogler^1,2, Joshua R Wheeler^2,3, Eric D Nguyen^2,4

¹Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO, USA.

Nature

|November 23, 2018

まとめ

TDP-43タンパク質の細胞プラズマ集積は,神経筋疾患において一般的です. 研究者らは,正常な筋肉再生には,TDP-43が一時的な"ミオ粒"を形成することが含まれていることを発見しました.

科学分野:

生物化学
分子生物学
神経科学

背景:

ALSやインクルージョンボディミオパシーのような神経筋疾患の特徴です.
TARDBPの変異はTDP-43の結合を引き起こしますが,ほとんどの患者は未知のメカニズムを示唆するワイルドタイプのTDP-43の結合を持っています.

研究の目的:

神経筋疾患における野生型TDP-43結合のメカニズムを調査する.
骨格筋におけるTDP-43の正常な機能と,疾患の病原性におけるその潜在的な役割を調査する.

主な方法:

マウスとヒトのモデルにおける骨格筋再生におけるTDP-43の役割を研究した.
TDP-43を含む細胞質の集合体 (ミオ粒) を特徴づけている.
ミオ粒子の形成,mRNAの結合,クリアランス,およびアミロイド線維の発芽の可能性を評価した.

主要な成果:

TDP-43は骨格筋の形成に不可欠であり,再生中に一時的なアミロイドのような"ミオ粒"を形成します.
これらのミオ粒子は,サルコメリックタンパク質に対するmRNAを結合し,筋肉が成熟するにつれてクリアされます.
ミオ粒子はTDP-43アミロイド繊維をインビトロで発酵させることができ,インクルージョンボディミオパシーマウスモデルでは上昇します.

結論:

ミオ粒子は,筋肉の再生中に TDP - 43 の正常な,一時的な集合体を表します.
常見の神経筋疾患における有毒なTDP-43アグレガートの主要な源は,ミオ粒子の組成またはクリアランスの不調である.

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