Department of Anatomy, Physiology and Pharmacology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada.
Department of Anatomy, Physiology and Pharmacology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada.
Neurosci Lett. 2020 Jan 18;716:134641. doi: 10.1016/j.neulet.2019.134641. Epub 2019 Nov 20.
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been well documented in glycolytic pathway. Independent of this, it has various other functions including stimulator of programmed cell death. Reports suggest that glutamate receptor AMPA type-2 subunit (GluA2) forms protein complex with GAPDH and internalized during excitotoxicity. Further, nuclear accumulation of GluA2 and GAPDH have been studied in neurological disorders like epilepsy and multiple sclerosis, and disruption of this complex rescued neurological symptoms such as astrogliosis, AMPA mediated excitotoxicity and p53 phosphorylation. On the other hand, study on ischemic rat model showed that nucleus translocated GAPDH binds with p53 leading to apoptosis. However, the molecular events underlying these processes remained to be established in Parkinson's disease (PD). The present study focused on investigating the levels of GAPDH, GluA2 and p53 in the nuclear fraction (NF) and total homogenate (TH) of substantia nigral (SN) region obtained from post-mortem PD brains and their age-matched controls. The level of caspase 3, an apoptotic marker and mediator for p53 induced cell death was also measured. A significant increase in nuclear GAPDH, GluA2 and p53 were observed in PD SN region, compared to the controls. Similarly, increased caspase 3 level was observed in PD SN region. Data obtained from the present study suggest that nuclear accumulation of GAPDH, GluA2 and p53 plays a key role in the pathophysiology of neuronal cell death in PD. Thus decreasing nuclear translocation of these death pro-death signaling markers may attenuate neurodegeneration that aids in the development of potential therapeutic targets in the management of PD.
甘油醛-3-磷酸脱氢酶（GAPDH）在糖酵解途径中已有很好的记载。除此之外，它还有各种其他功能，包括程序性细胞死亡的刺激剂。有报道称，谷氨酸受体 AMPA 型 2 亚基（GluA2）与 GAPDH 形成蛋白复合物，并在兴奋毒性时内化。此外，在癫痫和多发性硬化症等神经疾病中研究了 GluA2 和 GAPDH 的核内积累，并且破坏这种复合物可挽救神经症状，如星形胶质细胞增生、AMPA 介导的兴奋毒性和 p53 磷酸化。另一方面，对缺血性大鼠模型的研究表明，核转位 GAPDH 与 p53 结合导致细胞凋亡。然而，在帕金森病（PD）中，这些过程背后的分子事件仍有待确定。本研究重点研究了从帕金森病大脑死后的黑质（SN）区获得的核部分（NF）和总匀浆（TH）中 GAPDH、GluA2 和 p53 的水平及其年龄匹配的对照。还测量了凋亡标志物和 p53 诱导的细胞死亡的介质 caspase 3 的水平。与对照组相比，PD SN 区的核 GAPDH、GluA2 和 p53 水平显着增加。类似地，在 PD SN 区观察到 caspase 3 水平增加。本研究获得的数据表明，GAPDH、GluA2 和 p53 的核内积累在 PD 神经元细胞死亡的病理生理学中起关键作用。因此，减少这些死亡促进信号标志物的核易位可能会减轻神经退行性变，从而有助于开发 PD 管理中的潜在治疗靶点。
