Brain Health Research Centre, Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin P.O. Box 56, New Zealand.
Brain Health Research Centre, School of Pharmacy, University of Otago, Dunedin P.O. Box 56, New Zealand.
Int J Mol Sci. 2022 May 27;23(11):6039. doi: 10.3390/ijms23116039.
Altered arginine metabolism (including the polyamine system) has recently been implicated in the pathogenesis of tauopathies, characterised by hyperphosphorylated and aggregated microtubule-associated protein tau (MAPT) accumulation in the brain. The present study, for the first time, systematically determined the time-course of arginine metabolism changes in the P301S (PS19) mouse brain at 2, 4, 6, 8 and 12 months of age. The polyamines putrescine, spermidine and spermine are critically involved in microtubule assembly and stabilization. This study, therefore, further investigated how polyamine biosynthetic and catabolic enzymes changed in PS19 mice. There were general age-dependent increases of L-arginine, L-ornithine, putrescine and spermidine in the PS19 brain (particularly in the hippocampus and parahippocampal region). While this profile change clearly indicates a shift of arginine metabolism to favor polyamine production (a polyamine stress response), spermine levels were decreased or unchanged due to the upregulation of polyamine retro-conversion pathways. Our results further implicate altered arginine metabolism (particularly the polyamine system) in the pathogenesis of tauopathies. Given the role of the polyamines in microtubule assembly and stabilization, future research is required to understand the functional significance of the polyamine stress response and explore the preventive and/or therapeutic opportunities for tauopathies by targeting the polyamine system.
精氨酸代谢改变（包括多胺系统）最近被牵连到tau 病的发病机制中，tau 病的特征是脑内微管相关蛋白 tau（MAPT）过度磷酸化和聚集。本研究首次系统地确定了 P301S（PS19）小鼠大脑中精氨酸代谢变化的时间过程，在 2、4、6、8 和 12 个月大时进行了研究。多胺腐胺、亚精胺和精胺在微管组装和稳定中起着至关重要的作用。因此，本研究进一步研究了 PS19 小鼠中多胺生物合成和分解代谢酶如何变化。PS19 大脑中的 L-精氨酸、L-鸟氨酸、腐胺和亚精胺随着年龄的增长普遍增加（特别是在海马和旁海马区）。虽然这种特征性的变化清楚地表明了精氨酸代谢向有利于多胺产生的转变（多胺应激反应），但由于多胺反向转化途径的上调，精胺水平降低或不变。我们的结果进一步表明，改变的精氨酸代谢（特别是多胺系统）与 tau 病的发病机制有关。鉴于多胺在微管组装和稳定中的作用，需要进一步研究多胺应激反应的功能意义，并通过靶向多胺系统探索 tau 病的预防和/或治疗机会。
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