Neuromodulator Control of Energy Reserves in Dopaminergic Neurons.

The brain is a metabolically vulnerable organ as neurons have both high resting metabolic rates and the need for local rapid conversion of carbon sources to ATP during activity. Midbrain dopamine neurons are thought to be particularly vulnerable to metabolic perturbations, as a subset of these are the first to undergo degeneration in Parkinson’s disease (PD), a neurodegenerative disorder long suspected to be in part driven by deficits in mid-brain bioenergetics (1). In skeletal muscle, energy homeostasis under varying demands is achieved in part by its ability to rely on glycogen as a fuel store, whose conversion to ATP is under hormonal regulatory control. In neurons however the absence of easily observable glycogen granules has cast doubt on whether this fuel store is operational, even though brain neurons express the key regulatory enzymes associated with building or burning glycogen (2). We show here that that in primary mid brain dopaminergic neurons, glycogen availability is under the control of dopamine auto receptors (D2R), such that dopamine itself provides a signal to store glycogen. We find that when glycogen stores are present, they provide remarkable resilience to dopamine nerve terminal function under extreme hypometabolic conditions, but loss of this dopamine derived signal, or impairment of access to glycogen, makes them hypersensitive to fuel deprivation. These data show that neurons can use an extracellular cue to regulate local metabolism and suggest that loss of dopamine secretion might make dopamine neurons particularly subject to neurodegeneration driven by metabolic stress.大脑是一种代谢脆弱的器官，因为神经元既具有较高的静息代谢速率，又需要在活动期间快速将碳源局部转化为三磷酸腺苷（ATP）。中脑多巴胺神经元被认为对代谢扰动尤为易感——这类神经元中的一个亚群是帕金森病（PD）中最先发生退行性变的群体，而长期以来人们认为这种神经退行性疾病的部分诱因源自中脑生物能学缺陷(1)。在骨骼肌中，机体在不同需求下维持能量稳态的部分途径，是依赖糖原作为燃料储备——糖原向ATP的转化过程受激素调控。然而在神经元中，尽管脑神经元表达调控糖原合成与分解的关键酶类(2)，但由于难以观察到明显的糖原颗粒，学界对这类燃料储备是否具有功能性一直存在质疑。本研究显示，在原代中脑多巴胺神经元中，糖原的可获得性受多巴胺自身受体（D2R）调控，即多巴胺本身可作为信号触发糖原储存。我们发现，当存在糖原储备时，糖原可为多巴胺能神经末梢功能在极端低代谢条件下提供显著的抗损伤能力；但如果丧失该多巴胺衍生信号，或无法获取糖原，则会使神经元对燃料剥夺高度敏感。这些数据表明，神经元可通过胞外信号调控局部代谢，并提示多巴胺分泌缺失可能会使多巴胺神经元更易受到代谢应激驱动的退行性变影响。