BACKGROUND The microtubule-associated protein tau accumulates into toxic aggregates in multiple neurodegenerative diseases. We found previously that loss of D2-family dopamine receptors ameliorated tauopathy in multiple models including a Caenorhabditis elegans model of tauopathy. METHODS To better understand how loss of D2-family dopamine receptors can ameliorate tau toxicity, we screened a collection of C. elegans mutations in dopamine-related genes (n = 45) for changes in tau transgene-induced behavioral defects. These included many genes responsible for dopamine synthesis, metabolism, and signaling downstream of the D2 receptors. RESULTS We identified one dopamine synthesis gene, DOPA decarboxylase (DDC), as a suppressor of tau toxicity in tau transgenic worms. Loss of the C. elegans DDC gene, bas-1, ameliorated the behavioral deficits of tau transgenic worms, reduced phosphorylated and detergent-insoluble tau accumulation, and reduced tau-mediated neuron loss. Loss of function in other genes in the dopamine and serotonin synthesis pathways did not alter tau-induced toxicity; however, their function is required for the suppression of tau toxicity by bas-1. Additional loss of D2-family dopamine receptors did not synergize with bas-1 suppression of tauopathy phenotypes. CONCLUSIONS Loss of the DDC bas-1 reduced tau-induced toxicity in a C. elegans model of tauopathy, while loss of no other dopamine or serotonin synthesis genes tested had this effect. Because loss of activity upstream of DDC could reduce suppression of tau by DDC, this suggests the possibility that loss of DDC suppresses tau via the combined accumulation of dopamine precursor levodopa and serotonin precursor 5-hydroxytryptophan.

中文翻译：

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多巴脱羧酶调节 Tau 毒性

背景微管相关蛋白tau 在多种神经退行性疾病中积累成有毒聚集体。我们以前发现 D2 家族多巴胺受体的缺失改善了多种模型中的 tau 蛋白病，包括 tau 蛋白病的秀丽隐杆线虫模型。方法 为了更好地了解 D2 家族多巴胺受体的缺失如何改善 tau 毒性，我们筛选了多巴胺相关基因（n = 45）中的一组秀丽隐杆线虫突变，以了解 tau 转基因诱导的行为缺陷的变化。这些包括许多负责多巴胺合成、代谢和 D2 受体下游信号传导的基因。结果我们鉴定了一种多巴胺合成基因，即多巴脱羧酶 (DDC)，它是 tau 转基因蠕虫中 tau 毒性的抑制因子。秀丽隐杆线虫 DDC 基因 bas-1 的缺失，改善了 tau 转基因蠕虫的行为缺陷，减少了磷酸化和洗涤剂不溶性 tau 的积累，并减少了 tau 介导的神经元丢失。多巴胺和血清素合成途径中其他基因的功能丧失不会改变 tau 诱导的毒性；然而，它们的功能是抑制 bas-1 tau 毒性所必需的。D2 家族多巴胺受体的额外损失与 bas-1 对 tau 蛋白病表型的抑制没有协同作用。结论 DDC bas-1 的缺失降低了 tau 线虫模型中 tau 诱导的毒性，而其他多巴胺或血清素合成基因的缺失测试没有这种效果。因为 DDC 上游活性的丧失可以减少 DDC 对 tau 的抑制，