Tauopathies are a group of neurodegenerative diseases characterized by hyperphosphorylation of the microtubule-binding protein, tau, and typically feature axon impairment and synaptic dysfunction. Cyclin-dependent kinase5 (Cdk5) is a major tau kinase and its activity requires p35 or p25 regulatory subunits. P35 is subjected to rapid proteasomal degradation in its membrane-bound form and is cleaved by calpain under stress to a stable p25 form, leading to aberrant Cdk5 activation and tau hyperphosphorylation. The type Ib transmembrane protein RPS23RG1 has been implicated in Alzheimer’s disease (AD). However, physiological and pathological roles for RPS23RG1 in AD and other tauopathies are largely unclear. Herein, we observed retarded axon outgrowth, elevated p35 and p25 protein levels, and increased tau phosphorylation at major Cdk5 phosphorylation sites in Rps23rg1 knockout (KO) mice. Both downregulation of p35 and the Cdk5 inhibitor roscovitine attenuated tau hyperphosphorylation and axon outgrowth impairment in Rps23rg1 KO neurons. Interestingly, interactions between the RPS23RG1 carboxyl-terminus and p35 amino-terminus promoted p35 membrane distribution and proteasomal degradation. Moreover, P301L tau transgenic (Tg) mice showed increased tau hyperphosphorylation with reduced RPS23RG1 levels and impaired axon outgrowth. Overexpression of RPS23RG1 markedly attenuated tau hyperphosphorylation and axon outgrowth defects in P301L tau Tg neurons. Our results demonstrate the involvement of RPS23RG1 in tauopathy disorders, and implicate a role for RPS23RG1 in inhibiting tau hyperphosphorylation through homeostatic p35 degradation and suppression of Cdk5 activation. Reduced RPS23RG1 levels in tauopathy trigger aberrant Cdk5-p35 activation, consequent tau hyperphosphorylation, and axon outgrowth impairment, suggesting that RPS23RG1 may be a potential therapeutic target in tauopathy disorders.

Tauopathies 是一组以微管结合蛋白 tau 过度磷酸化为特征的神经退行性疾病，通常以轴突损伤和突触功能障碍为特征。细胞周期蛋白依赖性激酶 5 (Cdk5) 是一种主要的 tau 激酶，其活性需要 p35 或 p25 调节亚基。P35 在其膜结合形式中经历快速蛋白酶体降解，并在压力下被钙蛋白酶切割成稳定的 p25 形式，导致异常的 Cdk5 激活和 tau 过度磷酸化。Ib 型跨膜蛋白 RPS23RG1 与阿尔茨海默病 (AD) 相关。然而，RPS23RG1 在 AD 和其他 tauopathies 中的生理和病理作用在很大程度上尚不清楚。在此，我们观察到轴突生长延迟，p35 和 p25 蛋白水平升高，Rps23rg1基因敲除 (KO) 小鼠。p35 和 Cdk5 抑制剂 roscovitine 的下调都减弱了Rps23rg1 中的tau 过度磷酸化和轴突生长障碍KO神经元。有趣的是，RPS23RG1 羧基末端和 p35 氨基末端之间的相互作用促进了 p35 膜分布和蛋白酶体降解。此外，P301L tau 转基因 (Tg) 小鼠显示 tau 过度磷酸化增加，RPS​​23RG1 水平降低，轴突生长受损。RPS23RG1 的过表达显着减弱了 P301L tau Tg 神经元中的 tau 过度磷酸化和轴突生长缺陷。我们的结果表明 RPS23RG1 参与 tau 蛋白病变，并暗示 RPS23RG1 在通过稳态 p35 降解和抑制 Cdk5 激活来抑制 tau 过度磷酸化中的作用。tau 蛋白病中 RPS23RG1 水平降低触发异常 Cdk5-p35 激活，随之而来的 tau 蛋白过度磷酸化和轴突生长障碍，