Program in Neuroscience & Behavior, Mount Holyoke College, South Hadley, MA, USA.
Program in Neuroscience & Behavior, Mount Holyoke College, South Hadley, MA, USA.
Neurosci Lett. 2021 Jun 11;755:135937. doi: 10.1016/j.neulet.2021.135937. Epub 2021 Apr 25.
Tauopathies are a class of neurodegenerative diseases characterized by the abnormal phosphorylation and accumulation of the microtubule-associated protein, Tau. These diseases are associated with degeneration and dysfunction of the noradrenergic system, a critical regulator of memory, locomotion, and the fight or flight response. Though Tau pathology accumulates early in noradrenergic neurons, the relationship between noradrenaline signaling and tauopathy pathogenesis remains unclear. The fruit fly, Drosophila melanogaster, is a valuable model organism commonly used to investigate factors that promote Tau-mediated degeneration. Moreover, Drosophila contain the biogenic amine, octopamine, which is the functional homolog to noradrenaline. Using a Drosophila model of tauopathy, we conducted a candidate modifier screen targeting tyramine β hydroxylase (tβh), the enzyme that controls the production of octopamine in the fly, to determine if levels of this enzyme modulate Tau-induced degeneration in the fly eye. We found that genetic reduction of tβh suppresses Tau toxicity, independent of Tau phosphorylation. These findings show that reduction of tβh, a critical enzyme in the octopaminergic pathway, suppresses Tau pathogenicity and establishes an interaction that can be further utilized to determine the relationship between noradrenergic-like signaling and Tau toxicity in Drosophila.
tau 病是一类以微管相关蛋白 tau 的异常磷酸化和积累为特征的神经退行性疾病。这些疾病与去甲肾上腺素能系统的退化和功能障碍有关，去甲肾上腺素能系统是记忆、运动和战斗或逃跑反应的关键调节者。尽管 tau 病理学在去甲肾上腺素能神经元中早期积累，但去甲肾上腺素能信号与 tau 病发病机制之间的关系仍不清楚。果蝇，黑腹果蝇，是一种常用的模式生物，常用于研究促进 tau 介导的退化的因素。此外，果蝇含有生物胺章鱼胺，它是去甲肾上腺素的功能同源物。我们使用 tau 病的果蝇模型，针对 tyramine β hydroxylase（tβh）进行了候选修饰剂筛选，tβh 是控制果蝇中章鱼胺产生的酶，以确定这种酶的水平是否调节果蝇眼睛中的 Tau 诱导的退化。我们发现 tβh 的遗传减少抑制了 Tau 毒性，与 Tau 磷酸化无关。这些发现表明，减少 tβh，章鱼胺能途径中的关键酶，抑制 Tau 的致病性，并建立了一种相互作用，可以进一步用于确定去甲肾上腺素样信号与果蝇中 Tau 毒性之间的关系。
