tau 表达缺失可减轻与 α-突触核蛋白病相关的神经退行性变。

BACKGROUND: Neuronal dysfunction and degeneration linked to α-synuclein (αS) pathology is thought to be responsible for the progressive nature of Parkinson's disease and related dementia with Lewy bodies. Studies have indicated bidirectional pathological relationships between αS pathology and tau abnormalities. We recently showed that A53T mutant human αS (HuαS) can cause post-synaptic and cognitive deficits that require microtubule-associated protein tau expression. However, the role of tau in the development of αS pathology and subsequent neuronal dysfunction has been controversial. Herein, we set out to determine the role of tau in the onset and progression of αS pathology (α-synucleinopathy) using a transgenic mouse model of α-synucleinopathy lacking mouse tau expression. METHODS: Transgenic mice expressing A53T mutant HuαS (TgA53T) were crossed with mTau mice to generate TgA53T/mTau. To achieve more uniform induction of α-synucleinopathy in mice, we used intramuscular injections of αS preformed fibrils (PFF) in non-transgenic (nTg), TgA53T, TgA53T/mTau, and mTau mice. Motor behavior was analyzed at 70 days post inoculation (dpi) of PFF and tissues for biochemical and neuropathological analysis were collected at 40 dpi, 70 dpi, and end stage. RESULTS: Loss of tau expression significantly delayed the onset of motor deficits in the TgA53T model and the progression of α-synucleinopathy disease, as evidenced by a significant reduction in histopathological and behavioral markers of neurodegeneration and disease, and a significant improvement in survival. In vitro application of PFF to primary mouse hippocampal neurons demonstrated no changes in PFF uptake and processing or pS129 αS aggregation as a function of tau expression. However, PFF-induced neurotoxicity, including morphological deficits in nTg neurons, was prevented with tau removal. CONCLUSIONS: Collectively, our data suggest that tau is likely acting downstream of αS pathology to affect neuronal homeostasis and survival. This work further supports the investigation of tau in α-synucleinopathies to identify novel disease-modifying therapeutic strategies.

背景：与α-突触核蛋白（αS）病理学相关的神经元功能障碍和退化被认为是导致帕金森病和相关路易体痴呆进行性发展的原因。研究表明，αS 病理学和 tau 异常之间存在双向病理关系。我们最近表明，A53T 突变的人 αS（HuαS）可导致需要微管相关蛋白 tau 表达的突触后和认知缺陷。然而，tau 在 αS 病理学的发展和随后的神经元功能障碍中的作用一直存在争议。在此，我们着手使用缺乏小鼠 tau 表达的α-突触核蛋白病转基因小鼠模型来确定 tau 在 αS 病理学（α-突触核蛋白病）发病和进展中的作用。

方法：将表达 A53T 突变 HuαS（TgA53T）的转基因小鼠与 mTau 小鼠杂交，以生成 TgA53T/mTau。为了在小鼠中更均匀地诱导 α-突触核蛋白病，我们使用αS 预形成纤维（PFF）的肌肉内注射来感染非转基因（nTg）、TgA53T、TgA53T/mTau 和 mTau 小鼠。在 PFF 接种后 70 天（dpi）分析运动行为，并在 40 dpi、70 dpi 和终末期收集用于生化和神经病理学分析的组织。

结果：tau 表达缺失显著延迟了 TgA53T 模型运动缺陷的发作和 α-突触核蛋白病的进展，这表现在神经退行性和疾病的组织病理学和行为标志物显著减少，以及存活率显著提高。体外应用 PFF 到原代小鼠海马神经元中，tau 表达对 PFF 摄取和加工或 pS129αS 聚集没有影响。然而，PFF 诱导的神经毒性，包括 nTg 神经元的形态缺陷，在去除 tau 后得到了预防。

结论：总的来说，我们的数据表明 tau 可能是在 αS 病理学的下游起作用，以影响神经元的内稳态和存活。这项工作进一步支持了在α-突触核蛋白病中研究 tau，以确定新的疾病修饰治疗策略。