Neurosciences Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark.
Mol Neurobiol. 2020 Nov;57(11):4845-4855. doi: 10.1007/s12035-020-02061-7. Epub 2020 Aug 18.
Traumatic spinal cord injury (SCI) can result in substantial neurological impairment along with significant emotional and psychological distress. It is clear that there is profound neurodegeneration upon SCI, gradually spread to other spinal cord regions and brain areas. Despite extensive considerations, it remains uncertain how pathogenicity diffuses in the cord. It has been reported that tau protein abnormal hyperphosphorylation plays a central role in neurodegeneration triggered by traumatic brain injury (TBI). Tau is a microtubule-associated protein, heavily implicated in neurodegenerative diseases. Importantly, tau pathology spreads in a traumatic brain in a timely manner. In particular, we have recently demonstrated that phosphorylated tau at Thr231 exists in two distinct cis and trans conformations, in which that cis P-tau is extremely neurotoxic, has a prion nature, and spreads to various brain areas and cerebrospinal fluid (CSF) upon trauma. On the other hand, tau pathology, in particular hyperphosphorylation at Thr231, has been observed upon SCI. Taken these together, we conclude that cis pT231-tau may accumulate and spread in the spinal cord as well as CSF and diffuse tau pathology in the central nervous system (CNS). Moreover, antibody against cis P-tau can target intracellular cis P-tau and protect pathology spreading. Thus, considering cis P-tau as a driver of tau pathology and neurodegeneration upon SCI would open new windows toward understanding the disease development and early biomarkers. Furthermore, it would help us develop effective therapies for SCI patients.
创伤性脊髓损伤 (SCI) 可导致严重的神经功能障碍，同时伴有明显的情绪和心理困扰。很明显，SCI 后存在深刻的神经退行性变，逐渐扩散到其他脊髓区域和大脑区域。尽管进行了广泛的考虑，但致病性如何在脊髓中扩散仍不确定。据报道，tau 蛋白异常过度磷酸化在创伤性脑损伤 (TBI) 引发的神经退行性变中起核心作用。tau 是一种微管相关蛋白，与神经退行性疾病密切相关。重要的是，tau 病理学在创伤性大脑中及时传播。特别是，我们最近证明 Thr231 处磷酸化的 tau 存在两种不同的顺式和反式构象，其中顺式 P-tau 具有极强的神经毒性、朊病毒特性，并在创伤后扩散到各种大脑区域和脑脊液 (CSF)。另一方面，tau 病理学，特别是 Thr231 处的过度磷酸化，在 SCI 后也观察到。综上所述，我们得出结论，cis pT231-tau 可能在脊髓以及 CSF 中积累和传播，并在中枢神经系统 (CNS) 中扩散 tau 病理学。此外，针对 cis P-tau 的抗体可以靶向细胞内 cis P-tau 并保护病理学的扩散。因此，将 cis P-tau 视为 SCI 后 tau 病理学和神经退行性变的驱动因素，将为理解疾病发展和早期生物标志物开辟新的窗口。此外，它将帮助我们为 SCI 患者开发有效的治疗方法。
