Reduced PHOX2B stability causes axonal growth impairment in motor neurons with TARDBP mutations.
Reduced PHOX2B stability causes axonal growth impairment in motor neurons with TARDBP mutations.
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DOI：
10.1016/j.stemcr.2021.04.021
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发表时间：
2021-06-08
影响因子：
5.9
通讯作者：
Aoki M
中科院分区：
文献类型：
--
作者：
Mitsuzawa S;Suzuki N;Akiyama T;Ishikawa M;Sone T;Kawada J;Funayama R;Shirota M;Mitsuhashi H;Morimoto S;Ikeda K;Shijo T;Ohno A;Nakamura N;Ono H;Ono R;Osana S;Nakagawa T;Nishiyama A;Izumi R;Kaneda S;Ikeuchi Y;Nakayama K;Fujii T;Warita H;Okano H;Aoki M
肌萎缩侧索硬化症（ALS）是一种成人发病的不可治愈的运动神经元（MN）疾病。ALS中选择性MN脆弱性的原因尚不清楚。轴突病变是ALS的最早迹象之一。我们寻找新的调节基因在人类MN轴突缩短的影响TARDBP突变。在人源诱导多能干细胞（iPSC）衍生MN的轴突区室中存在的RNA的转录组分析中，PHOX 2B（配对样同源框蛋白2B）在TARDBP突变体轴突中显示出较低的表达，这与轴突qPCR和原位杂交一致。在TARDBP突变MN中，PH 0X 2B mRNA稳定性降低。此外，PH 0X 2B敲低减少了人MN中的神经突长度。最后，phox 2b敲低斑马鱼诱导短脊髓轴突和受损的逃避反应。已知PHOX 2B在ALS进展后维持的其他类型的神经元中高度表达。总的来说，TARDBP突变诱导轴突弹性的丧失，这是由PHOX 2B下调介导的重要ALS相关表型。从具有TARDBP p.G376D突变的家族性ALS建立人iPSC，通过RNA测序鉴定PHOX 2B mRNA在TARDBP突变MN中减少，PHOX 2B mRNA与TDP-43结合，并且其在TARDBP突变MN中的稳定性降低，PHOX 2B敲低减少了轴突长度并损害了体内/体外运动功能。具有TARDBP突变和PHOX 2B敲低的衍生MN在体内和体外减少了神经突长度并损害了运动功能。已知PHOX 2B在ALS进展后维持的其他类型的神经元中高度表达。总的来说，TARDBP突变诱导的轴突弹性损失，一个重要的ALS相关表型，是由PHOX 2B下调介导的。
Amyotrophic lateral sclerosis (ALS) is an adult-onset incurable motor neuron (MN) disease. The reasons for selective MN vulnerability in ALS are unknown. Axonal pathology is among the earliest signs of ALS. We searched for novel modulatory genes in human MN axon shortening affected by TARDBP mutations. In transcriptome analysis of RNA present in the axon compartment of human-derived induced pluripotent stem cell (iPSC)-derived MNs, PHOX2B (paired-like homeobox protein 2B) showed lower expression in TARDBP mutant axons, which was consistent with axon qPCR and in situ hybridization. PHOX2B mRNA stability was reduced in TARDBP mutant MNs. Furthermore, PHOX2B knockdown reduced neurite length in human MNs. Finally, phox2b knockdown in zebrafish induced short spinal axons and impaired escape response. PHOX2B is known to be highly express in other types of neurons maintained after ALS progression. Collectively, TARDBP mutations induced loss of axonal resilience, which is an important ALS-related phenotype mediated by PHOX2B downregulation. Human iPSCs were established from a familial ALS with the TARDBP p.G376D mutation PHOX2B mRNA was identified to be decreased in TARDBP mutant MNs by RNA sequencing PHOX2B mRNA bind to TDP-43 and its stability was reduced in TARDBP mutant MNs PHOX2B knockdown reduced neurite length and impaired motor functions in vivo/vitro A novel modulatory gene PHOX2B decreased in human iPSC-derived MNs with TARDBP mutations and PHOX2B knockdown reduced neurite length and impaired motor functions in vivo and vitro. PHOX2B is known that highly express in other type of neurons maintained after the progression of ALS. Collectively, TARDBP mutations induced loss of axonal resilience, an important ALS-related phenotype, is mediated by PHOX2B downregulation.
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影响因子：
5.3
作者：
Kapeli K;Martinez FJ;Yeo GW
通讯作者：
Yeo GW
影响因子：
4.8
作者：
Cargnin, F;Flora, A;Fornasari, D
通讯作者：
Fornasari, D
DOI：
10.1074/jbc.m115.679027
发表时间：
2016-06-17
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Di Lascio S;Belperio D;Benfante R;Fornasari D
通讯作者：
Fornasari D
影响因子：
5.9
作者：
Fujimori K;Matsumoto T;Kisa F;Hattori N;Okano H;Akamatsu W
通讯作者：
Akamatsu W
影响因子：
15.9
作者：
Nagashimada, Mayumi;Ohta, Hiroshi;Enomoto, Hideki
通讯作者：
Enomoto, Hideki