Department of Neuroscience, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, 560029, India.
Department of Neurophysiology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, 560029, India.
Neurotox Res. 2019 Jul;36(1):27-38. doi: 10.1007/s12640-019-00036-8. Epub 2019 Apr 16.
Alterations in the basal ganglia circuitry are critical events in the pathophysiology of Parkinson's disease (PD). We earlier compared MPTP-susceptible C57BL/6J and MPTP-resistant CD-1 mice to understand the differential prevalence of PD in different ethnic populations like Caucasians and Asian-Indians. The MPTP-resistant CD-1 mice had 33% more nigral neurons and lost only 15-17% of them following MPTP administration. In addition to other cytomorphological features, their basal ganglia neurons had higher calcium-buffering protein levels. During disease pathogenesis as well as in MPTP-induced parkinsonian models, the loss of nigral neurons is associated with reduction in mitochondrial complex-1. Under these conditions, mitochondria respond by undergoing fusion or fission. 17β-hydroxysteroid type 10, i.e., hydroxysteroid dehydrogenase10 (HSD10) and dynamin-related peptide1 (Drp1) are proteins involved in mitochondrial hyperfusion and fission, respectively. Each plays an important role in mitochondrial structure and homeostasis. Their role in determining susceptibility to the neurotoxin MPTP in basal ganglia is however unclear. We studied their expression using immunohistochemistry and Western blotting in the dorsolateral striatum, ventral tegmental area, and substantia nigra pars compacta (SNpc) of C57BL/6J and CD-1 mice. In the SNpc, which exhibits more neuron loss following MPTP, C57BL/6J had higher baseline Drp1 levels; suggesting persistence of fission under normal conditions. Whereas, HSD10 levels increased in CD-1 following MPTP administration. This suggests mitochondrial hyperfusion, as an attempt towards neuroprotection. Thus, the baseline differences in HSD10 and DRP1 levels as well as their contrasting MPTP-responses may be critical determinants of the magnitude of neuronal loss/survival. Similar differences may determine the variable susceptibility to PD in humans.
基底神经节回路的改变是帕金森病（PD）病理生理学中的关键事件。我们之前比较了易患 MPTP 的 C57BL/6J 和不易患 MPTP 的 CD-1 小鼠，以了解不同种族人群（如白人和亚洲印度人）中 PD 的不同流行率。不易患 MPTP 的 CD-1 小鼠的黑质神经元多 33%，并且在给予 MPTP 后仅损失 15-17%。除了其他细胞形态特征外，它们的基底神经节神经元具有更高的钙缓冲蛋白水平。在疾病发病机制以及 MPTP 诱导的帕金森模型中，黑质神经元的丢失与线粒体复合物 1 的减少有关。在这些情况下，线粒体通过融合或裂变来响应。17β-羟甾类 10 型，即羟甾类脱氢酶 10（HSD10）和动力相关蛋白肽 1（Drp1），分别是参与线粒体过度融合和裂变的蛋白质。两者在维持线粒体结构和稳态方面都发挥着重要作用。然而，它们在决定对基底神经节神经毒素 MPTP 的易感性方面的作用尚不清楚。我们使用免疫组织化学和 Western blot 法在 C57BL/6J 和 CD-1 小鼠的背外侧纹状体、腹侧被盖区和黑质致密部（SNpc）中研究了它们的表达。在 SNpc 中，MPTP 给药后神经元丢失更多，C57BL/6J 具有更高的基础 Drp1 水平；表明在正常情况下存在分裂的持久性。而，在给予 MPTP 后，CD-1 中的 HSD10 水平增加。这表明线粒体过度融合，作为神经保护的一种尝试。因此，基础 HSD10 和 DRP1 水平的差异以及它们对 MPTP 的相反反应可能是神经元丢失/存活的关键决定因素。类似的差异可能决定了人类对 PD 的易感性。
