Stubbs Katy, Batchelor Ben, Sivanantharajah Lovesha, Sealey Megan, Ramirez-Moreno Miguel, Ruiz Eva, Richardson Brad, Perry Victor H, Newman Tracey A, Mudher Amritpal
School of Biological Sciences, Faculty of Environment and Life Sciences, University of Southampton, Highfield Campus, Southampton, SO17 1BJ, UK.
School of Biological Sciences, Bangor University, Bangor LL57 2UW, UK.
Brain Commun. 2023 Mar 9;5(2):fcad052. doi: 10.1093/braincomms/fcad052. eCollection 2023.
Tauopathy is characterized by neuronal dysfunction and degeneration occurring as a result of changes to the microtubule-associated protein tau. The neuronal changes evident in tauopathy bear striking morphological resemblance to those reported in models of Wallerian degeneration. The mechanisms underpinning Wallerian degeneration are not fully understood although it can be delayed by the expression of the slow Wallerian degeneration (Wld) protein, which has also been demonstrated to delay axonal degeneration in some models of neurodegenerative disease. Given the morphological similarities between tauopathy and Wallerian degeneration, this study investigated whether tau-mediated phenotypes can be modulated by co-expression of Wld. In a model of tauopathy in which expression of human 0N3R tau protein leads to progressive age-dependent phenotypes, Wld was expressed with and without activation of the downstream pathway. The olfactory receptor neuron circuit was used for these studies in adults, and the larval motor neuron system was employed in larvae. Tau phenotypes studied included neurodegeneration, axonal transport, synaptic deficits and locomotor behaviour. Impact on total tau was ascertained by assessing total, phosphorylated and misfolded tau levels by immunohistochemistry. Activation of the pathway downstream of Wld completely suppressed tau-mediated degeneration. This protective effect was evident even if the pathway downstream of Wld was activated several weeks after tau-mediated degeneration had become established. Though total tau levels were not altered, the protected neurons displayed significantly reduced MC1 immunoreactivity suggestive of clearance of misfolded tau, as well as a trend for a decline in tau species phosphorylated at the AT8 and PHF1 epitopes. In contrast, Wld expression without activation of the downstream protective pathway did not rescue tau-mediated degeneration in adults or improve tau-mediated neuronal dysfunction including deficits in axonal transport, synaptic alterations and locomotor behaviour in tau-expressing larvae. This collectively implies that the pathway mediating the protective effect of Wld intersects with the mechanism(s) of degeneration initiated by tau and can effectively halt tau-mediated degeneration at both early and late stages. Understanding the mechanisms underpinning this protection could identify much-needed disease-modifying targets for tauopathies.
tau蛋白病的特征是由于微管相关蛋白tau发生变化而导致神经元功能障碍和退化。tau蛋白病中明显的神经元变化与沃勒变性模型中报道的变化在形态上极为相似。尽管慢沃勒变性（Wld）蛋白的表达可以延迟沃勒变性，并且在一些神经退行性疾病模型中也已证明其可延迟轴突变性，但支撑沃勒变性的机制尚未完全明确。鉴于tau蛋白病与沃勒变性在形态上的相似性，本研究调查了Wld的共表达是否可以调节tau介导的表型。在一个tau蛋白病模型中，人类0N3R tau蛋白的表达会导致与年龄相关的渐进性表型，分别在激活和未激活下游通路的情况下表达Wld。在成体中使用嗅觉受体神经元回路进行这些研究，在幼虫中采用幼虫运动神经元系统。所研究的tau表型包括神经退行性变、轴突运输、突触缺陷和运动行为。通过免疫组织化学评估总tau、磷酸化tau和错误折叠tau的水平，以确定对总tau的影响。Wld下游通路的激活完全抑制了tau介导的退化。即使在tau介导的退化已经形成数周后激活Wld下游通路，这种保护作用仍然明显。尽管总tau水平没有改变，但受保护的神经元显示出MC1免疫反应性显著降低，提示错误折叠的tau被清除，并且在AT8和PHF1表位磷酸化的tau种类也有下降趋势。相比之下，在未激活下游保护通路的情况下表达Wld并不能挽救成体中tau介导的退化，也不能改善tau介导的神经元功能障碍，包括tau表达幼虫的轴突运输缺陷、突触改变和运动行为。这总体上意味着介导Wld保护作用的通路与tau引发的退化机制相交，并且可以在早期和晚期有效阻止tau介导的退化。了解这种保护作用的机制可以为tau蛋白病确定急需的疾病修饰靶点。
