Dahl Russell
Neurodon LLC, 5700 Tanager St., Schererville, IN 46375, USA.
Bioorg Med Chem. 2017 Jan 1;25(1):53-57. doi: 10.1016/j.bmc.2016.10.008. Epub 2016 Oct 12.
Endoplasmic reticulum (ER) stress is intimately linked to Parkinson's disease (PD) pathophysiology. Disrupted intracellular calcium homeostasis is a major cause of the ER stress seen in dopaminergic neurons, leading to the cell death and subsequent loss of movement and coordination in patients. Dysfunctional calcium handling proteins play a major role in the promulgation of ER stress in PD. Specifically, compromised sarco/endoplasmic reticulum Ca-ATPase (SERCA) has been identified as a major cause of ER stress and neuron loss in PD. We have identified a small molecule activator of SERCA that increases ER calcium content, rescues neurons from ER stress-induced cell death in vitro, and shows significant efficacy in the rat 6-hydroxydopamine (6-OHDA) model of PD. Together, these results support targeting SERCA activation as a viable strategy to develop disease-modifying therapeutics for PD.
内质网（ER）应激与帕金森病（PD）的病理生理学密切相关。细胞内钙稳态的破坏是多巴胺能神经元中内质网应激的主要原因，导致患者细胞死亡以及随后的运动和协调能力丧失。功能失调的钙处理蛋白在帕金森病内质网应激的发生中起主要作用。具体而言，肌浆网/内质网钙-ATP酶（SERCA）功能受损已被确定为帕金森病内质网应激和神经元丢失的主要原因。我们已经鉴定出一种SERCA小分子激活剂，它能增加内质网钙含量，在体外将神经元从内质网应激诱导的细胞死亡中拯救出来，并且在帕金森病大鼠6-羟基多巴胺（6-OHDA）模型中显示出显著疗效。总之，这些结果支持将SERCA激活作为一种可行的策略，来开发用于帕金森病的疾病修饰疗法。
