Loss of mouse Stmn2 function causes motor neuropathy.
Loss of mouse Stmn2 function causes motor neuropathy.
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DOI：
10.1016/j.neuron.2022.02.011
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发表时间：
2022-05-18
期刊：
影响因子：
16.2
通讯作者：
Eggan, Kevin
中科院分区：
文献类型：
--
作者：
San Juan, Irune Guerra;Nash, Leslie A.;Smith, Kevin S.;Leyton-Jaimes, Marcel F.;Qian, Menglu;Klim, Joseph R.;Limone, Francesco;Dorr, Alexander B.;Couto, Alexander;Pintacuda, Greta;Joseph, Brian J.;Whisenant, D. Eric;Noble, Caroline;Melnik, Veronika;Potter, Deirdre;Holmes, Amie;Burberry, Aaron;Verhage, Matthijs;Eggan, Kevin
肌萎缩侧索硬化症（ALS）的特征在于运动神经元变性，伴随RNA结合蛋白TDP 43的异常积累和功能丧失。到目前为止，TDP 43功能丧失在多大程度上直接导致运动系统功能障碍仍然没有解决。在这里，我们采用基因编辑来询问TDP 43调节基因STMN 2的小鼠直系同源物是否在维持运动系统方面具有重要功能。马赛克创始人和纯合子功能丧失的Stmn 2小鼠表现出神经肌肉接头去神经支配和断裂，导致肌肉萎缩和运动行为受损，伴随着脊髓中神经元微管动力学的不平衡。通过BAC转基因引入人STMN 2足以挽救在Stmn 2突变小鼠中观察到的这些运动表型。总的来说，我们的研究结果表明，破坏一个单一的TDP 43调节RNA的直系同源物足以引起实质性的运动功能障碍，这表明TDP 43功能的破坏可能是ALS的一个贡献者。TDP 43调节基因STMN 2提供了TDP 43功能障碍与ALS中观察到的运动神经病之间的潜在联系。Guerra圣胡安，Nash等人证明小鼠Stmn 2对于维持体内正常运动功能是必不可少的;其缺陷导致神经肌肉接头去神经支配、肌肉萎缩和运动行为受损。
Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron degeneration accompanied by aberrant accumulation and loss-of-function of the RNA-binding protein, TDP43. Thus far it remains unresolved to what extent TDP43 loss-of-function directly contributes to motor system dysfunction. Here, we employed gene editing to ask whether the mouse ortholog of the TDP43 regulated gene, STMN2, has an important function in maintaining the motor system. Both mosaic founders and homozygous loss-of-function Stmn2 mice exhibited neuromuscular junction denervation and fragmentation, resulting in muscle atrophy and impaired motor behavior, accompanied by an imbalance in neuronal microtubule dynamics in the spinal cord. Introduction of human STMN2 through BAC transgenics was sufficient to rescue these motor phenotypes observed in Stmn2 mutant mice. Collectively, our results demonstrate that disrupting the ortholog of a single TDP43-regulated RNA is sufficient to cause substantial motor dysfunction, indicating that disruption of TDP43 function is likely a contributor to ALS. The TDP43-regulated gene STMN2, provides a potential connection between TDP43 dysfunction and motor neuropathy as observed in ALS. Guerra San Juan, Nash et al. demonstrate that mouse Stmn2 is essential for maintaining normal motor function in vivo; its deficiency results in neuromuscular junction denervation, muscle atrophy and impaired motor behavior.
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影响因子：
5.3
作者：
Fischer, LR;Culver, DG;Glass, JD
通讯作者：
Glass, JD
影响因子：
17.1
作者：
Burberry A;Suzuki N;Wang JY;Moccia R;Mordes DA;Stewart MH;Suzuki-Uematsu S;Ghosh S;Singh A;Merkle FT;Koszka K;Li QZ;Zon L;Rossi DJ;Trowbridge JJ;Notarangelo LD;Eggan K
通讯作者：
Eggan K
影响因子：
5.1
作者：
Feneberg E;Gray E;Ansorge O;Talbot K;Turner MR
通讯作者：
Turner MR
影响因子：
3.5
作者：
Ash, Peter E. A.;Zhang, Yong-Jie;Link, Christopher D.
通讯作者：
Link, Christopher D.
DOI：
10.15252/embj.201798684
发表时间：
2018-06-01
期刊：
The EMBO journal
影响因子：
--
作者：
Fratta P;Sivakumar P;Humphrey J;Lo K;Ricketts T;Oliveira H;Brito-Armas JM;Kalmar B;Ule A;Yu Y;Birsa N;Bodo C;Collins T;Conicella AE;Mejia Maza A;Marrero-Gagliardi A;Stewart M;Mianne J;Corrochano S;Emmett W;Codner G;Groves M;Fukumura R;Gondo Y;Lythgoe M;Pauws E;Peskett E;Stanier P;Teboul L;Hallegger M;Calvo A;Chiò A;Isaacs AM;Fawzi NL;Wang E;Housman DE;Baralle F;Greensmith L;Buratti E;Plagnol V;Fisher EM;Acevedo-Arozena A
通讯作者：
Acevedo-Arozena A