Expression of Low Level of VPS35-mCherry Fusion Protein Diminishes Vps35 Depletion Induced Neuron Terminal Differentiation Deficits and Neurodegenerative Pathology, and Prevents Neonatal Death.
Expression of Low Level of VPS35-mCherry Fusion Protein Diminishes Vps35 Depletion Induced Neuron Terminal Differentiation Deficits and Neurodegenerative Pathology, and Prevents Neonatal Death.
复制标题
DOI：
10.3390/ijms22168394
复制
发表时间：
2021-08-04
影响因子：
5.6
通讯作者：
Xiong WC
中科院分区：
文献类型：
--
作者：
Zhao Y;Tang F;Lee D;Xiong WC
Vps35（液泡蛋白分选35）是由Vps35、Vps26、Vps29三聚体和分选蛋白连接蛋白二聚体组成的逆转录物的关键组分。功能失调的Vps35/retromer被认为是各种神经退行性疾病发展的危险因素。选择性敲除Neurod6-Cre+锥体神经元Vps35的Vps35Neurod6小鼠，表现出皮层和海马神经元树突和轴突终末分化的年龄依赖性损伤，神经退行性病理（即P62和Tdp43 （TAR dna结合蛋白43）蛋白增加，细胞死亡和反应性胶质增生），以及新生儿死亡。这些表型之间的关系和潜在的机制在很大程度上仍不清楚。在这里，我们提供的证据表明，VPS35-mCherry融合蛋白在Vps35Neurod6小鼠中的低水平表达可以以年龄依赖的方式减少表型。具体来说，我们已经产生了一个条件转基因小鼠系，LSL-Vps35-mCherry，它以cre依赖的方式表达VPS35-mCherry融合蛋白。将LSL-Vps35-mCherry与Vps35Neurod6杂交获得TgVPS35-mCherry， Vps35Neurod6小鼠在新生期可预防新生儿死亡，减少树突状形态发生缺陷和胶质细胞增生，但在成年期无此作用。进一步研究发现，Vps35- mcherry转基因表达较低，Vps35 mRNA的表达水平仅为对照小鼠Vps35 mRNA的~ 5-7%。如此低水平的VPS35-mCherry可以恢复新生儿年龄时其他逆转录成分（Vps26a和Vps29）的数量（P14）。重要的是，存活的成年TgVps35-mCherry出现了神经退行性病理；Vps35Neurod6老鼠。这些结果表明，低水平的Vps35 - mcherry融合蛋白足以减少新生龄Vps35 - neurod6小鼠的表型，验证了神经元Vps35在稳定逆转录复合物蛋白中的关键作用，并支持Vps35作为神经退行性疾病潜在治疗靶点的观点。
Vps35 (vacuolar protein sorting 35) is a key component of retromer that consists of Vps35, Vps26, and Vps29 trimers, and sortin nexin dimers. Dysfunctional Vps35/retromer is believed to be a risk factor for development of various neurodegenerative diseases. Vps35Neurod6 mice, which selectively knock out Vps35 in Neurod6-Cre+ pyramidal neurons, exhibit age-dependent impairments in terminal differentiation of dendrites and axons of cortical and hippocampal neurons, neuro-degenerative pathology (i.e., increases in P62 and Tdp43 (TAR DNA-binding protein 43) proteins, cell death, and reactive gliosis), and neonatal death. The relationships among these phenotypes and the underlying mechanisms remain largely unclear. Here, we provide evidence that expression of low level of VPS35-mCherry fusion protein in Vps35Neurod6 mice could diminish the phenotypes in an age-dependent manner. Specifically, we have generated a conditional transgenic mouse line, LSL-Vps35-mCherry, which expresses VPS35-mCherry fusion protein in a Cre-dependent manner. Crossing LSL-Vps35-mCherry with Vps35Neurod6 to obtain TgVPS35-mCherry, Vps35Neurod6 mice prevent the neonatal death and diminish the dendritic morphogenesis deficit and gliosis at the neonatal, but not the adult age. Further studies revealed that the Vps35-mCherry transgene expression was low, and the level of Vps35 mRNA comprised only ~5–7% of the Vps35 mRNA of control mice. Such low level of VPS35-mCherry could restore the amount of other retromer components (Vps26a and Vps29) at the neonatal age (P14). Importantly, the neurodegenerative pathology presented in the survived adult TgVps35-mCherry; Vps35Neurod6 mice. These results demonstrate the sufficiency of low level of VPS35-mCherry fusion protein to diminish the phenotypes in Vps35Neurod6 mice at the neonatal age, verifying a key role of neuronal Vps35 in stabilizing retromer complex proteins, and supporting the view for Vps35 as a potential therapeutic target for neurodegenerative diseases.
登录
查看更多内容
影响因子：
4.2
作者：
Chu, Jin;Pratico, Domenico
通讯作者：
Pratico, Domenico
影响因子：
14.8
作者：
Mecozzi, Vincent J.;Berman, Diego E.;Simoes, Sabrina;Vetanovetz, Chris;Awal, Mehraj R.;Patel, Vivek M.;Schneider, Remy T.;Petsko, Gregory A.;Ringe, Dagmar;Small, Scott A.
通讯作者：
Small, Scott A.
影响因子：
5.3
作者：
Kasu YAT;Alemu S;Lamari A;Loew N;Brower CS
通讯作者：
Brower CS
DOI：
10.1016/j.bbrc.2010.10.121
发表时间：
2010-12-10
影响因子：
3.1
作者：
Kim, Ekyune;Lee, Youngjeon;Chang, Kyu-Tae
通讯作者：
Chang, Kyu-Tae
影响因子：
7.2
作者：
Burd, Christopher;Cullen, Peter J.
通讯作者：
Cullen, Peter J.