Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore; Department of Physiology, National University of Singapore, Singapore; Department of Research, National Neuroscience Institute, Singapore.
Department of Research, National Neuroscience Institute, Singapore.
Neurobiol Dis. 2021 Dec;161:105560. doi: 10.1016/j.nbd.2021.105560. Epub 2021 Nov 10.
Emerging studies implicate energy dysregulation as an underlying trigger for Parkinson's disease (PD), suggesting that a better understanding of the molecular pathways governing energy homeostasis could help elucidate therapeutic targets for the disease. A critical cellular energy regulator is AMP kinase (AMPK), which we have previously shown to be protective in PD models. However, precisely how AMPK function impacts on dopaminergic neuronal survival and disease pathogenesis remains elusive. Here, we showed that Drosophila deficient in AMPK function exhibits PD-like features, including dopaminergic neuronal loss and climbing impairment that progress with age. We also created a tissue-specific AMPK-knockout mouse model where the catalytic subunits of AMPK are ablated in nigral dopaminergic neurons. Using this model, we demonstrated that loss of AMPK function promotes dopaminergic neurodegeneration and associated locomotor aberrations. Accompanying this is an apparent reduction in the number of mitochondria in the surviving AMPK-deficient nigral dopaminergic neurons, suggesting that an impairment in mitochondrial biogenesis may underlie the observed PD-associated phenotypes. Importantly, the loss of AMPK function enhances the susceptibility of nigral dopaminergic neurons in these mice to 6-hydroxydopamine-induced toxicity. Notably, we also found that AMPK activation is reduced in post-mortem PD brain samples. Taken together, these findings highlight the importance of neuronal energy homeostasis by AMPK in PD and position AMPK pathway as an attractive target for future therapeutic exploitation.
新兴研究表明，能量失调是帕金森病（PD）的潜在触发因素，这表明更好地了解调节能量稳态的分子途径可能有助于阐明该疾病的治疗靶点。一种关键的细胞能量调节剂是 AMP 激酶（AMPK），我们之前已经表明它在 PD 模型中具有保护作用。然而，AMPK 功能如何影响多巴胺能神经元的存活和疾病发病机制仍然难以捉摸。在这里，我们表明，缺乏 AMPK 功能的果蝇表现出类似 PD 的特征，包括多巴胺能神经元丢失和随年龄增长而进展的攀爬障碍。我们还创建了一种组织特异性 AMPK 敲除小鼠模型，其中 AMPK 的催化亚基在黑质多巴胺能神经元中被剔除。使用该模型，我们证明了 AMPK 功能的丧失会促进多巴胺能神经退行性变和相关的运动异常。伴随着这一点的是，存活的 AMPK 缺陷性黑质多巴胺能神经元中的线粒体数量明显减少，这表明线粒体生物发生的损害可能是观察到的与 PD 相关表型的基础。重要的是，AMPK 功能的丧失会增加这些小鼠中黑质多巴胺能神经元对 6-羟多巴胺诱导的毒性的易感性。值得注意的是，我们还发现 AMPK 激活在死后 PD 大脑样本中减少。总之，这些发现强调了 AMPK 在 PD 中神经元能量稳态的重要性，并将 AMPK 途径定位为未来治疗开发的有吸引力的靶点。
