Neuroscience Center of Excellence, Department of Cell Biology and Anatomy, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
Aging Cell. 2021 Nov;20(11):e13493. doi: 10.1111/acel.13493. Epub 2021 Oct 9.
Dopaminergic neurons (DANs) are essential modulators for brain functions involving memory formation, reward processing, and decision-making. Here I demonstrate a novel and important function of the DANs in regulating aging and longevity. Overexpressing the putative scaffolding protein Mask in two small groups of DANs in flies can significantly extend the lifespan in flies and sustain adult locomotor and fecundity at old ages. This Mask-induced beneficial effect requires dopaminergic transmission but cannot be recapitulated by elevating dopamine production alone in the DANs. Independent activation of Gα in the same two groups of DANs via the drug-inducible DREADD system also extends fly lifespan, further indicating the connection of specific DANs to aging control. The Mask-induced lifespan extension appears to depend on the function of Mask to regulate microtubule (MT) stability. A structure-function analysis demonstrated that the ankyrin repeats domain in the Mask protein is both necessary for regulating MT stability (when expressed in muscles and motor neurons) and sufficient to prolong longevity (when expressed in the two groups of DANs). Furthermore, DAN-specific overexpression of Unc-104 or knockdown of p150 , two independent interventions previously shown to impact MT dynamics, also extends lifespan in flies. Together, these data demonstrated a novel DANs-dependent mechanism that, upon the tuning of their MT dynamics, modulates systemic aging and longevity in flies.
多巴胺能神经元（DANs）是参与记忆形成、奖励处理和决策等大脑功能的重要调节因子。在这里，我展示了 DANs 在调节衰老和长寿方面的一个新的重要功能。在果蝇的两个小群 DANs 中过表达假定的支架蛋白 Mask ，可以显著延长果蝇的寿命，并维持老年期的成年运动能力和繁殖力。这种 Mask 诱导的有益效果需要多巴胺能传递，但不能仅通过提高 DANs 中的多巴胺产生来再现。通过药物诱导的 DREADD 系统在同一两组 DANs 中独立激活 Gα，也能延长果蝇的寿命，进一步表明特定 DANs 与衰老控制有关。Mask 诱导的寿命延长似乎依赖于 Mask 调节微管（MT）稳定性的功能。结构功能分析表明，Mask 蛋白中的锚蛋白重复结构域既对调节 MT 稳定性是必需的（当在肌肉和运动神经元中表达时），也足以延长寿命（当在两组 DANs 中表达时）。此外，以前显示影响 MT 动力学的 Unc-104 的 DANs 特异性过表达或 p150 的敲低，也能延长果蝇的寿命。总之，这些数据表明了一种新的 DANs 依赖性机制，通过调节它们的 MT 动力学，调节果蝇的全身衰老和长寿。
