Mondal Rupsha, Banerjee Chayan, Nandy Sumangal, Roy Moumita, Chakraborty Joy
CSIR-Indian Institute of Chemical Biology, Kolkata, 700032, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
Cell Biosci. 2023 Aug 1;13(1):140. doi: 10.1186/s13578-023-01068-6.
Parkinson's disease (PD), a highly prevalent neuro-motor disorder is caused due to progressive loss of dopaminergic (DAergic) neurons at substantia nigra region of brain. This leads to depleted dopamine (DA) content at striatum, thus affecting the fine tuning of basal ganglia. In patients, this imbalance is manifested by akinesia, catalepsy and tremor. PD associated behavioral dysfunctions are frequently mitigated by l-DOPA (LD) therapy, a precursor for DA synthesis. Due to progressive neurodegeneration, LD eventually loses applicability in PD. Although DA is cytotoxic, it is unclear whether LD therapy can accelerate PD progression or not. LD itself does not lead to neurodegeneration in vivo, but previous reports demonstrate that LD treatment mediated excess DA can potentiate neurotoxicity when PD associated genetic or epigenetic aberrations are involved. So, minimizing DA toxicity during the therapy is an absolute necessity to halt or slowdown PD progression. The two major contributing factors associated with DA toxicity are: degradation by Monoamine oxidase and DAquinone (DAQ) formation.
Here, we report that apoptotic mitochondrial fragmentation via Calcineurin (CaN)-DRP1 axis is a common downstream event for both these initial cues, inhibiting which can protect cells from DA toxicity comprehensively. No protective effect is observed, in terms of cell survival when only PxIxIT domain of CaN is obstructed, demonstrating the importance to block DRP1-CaN axis specifically. Further, evaluation of the impact of DA exposure on PD progression in a mice model reveal that LD mediated behavioral recovery diminishes with time, mostly because of continued DAergic cell death and dendritic spine loss at striatum. CaN inhibition, alone or in combination with LD, offer long term behavioral protection. This protective effect is mediated specifically by hindering CaN-DRP1 axis, whereas inhibiting interaction between CaN and other substrates, including proteins involved in neuro-inflammation, remained ineffective when LD is co-administered.
In this study, we conclude that DA toxicity can be circumvented by CaN inhibition and it can mitigate PD related behavioral aberrations by protecting neuronal architecture at striatum. We propose that CaN inhibitors might extend the therapeutic efficacy of LD treatment.
帕金森病（PD）是一种高度流行的神经运动障碍，由大脑黑质区域多巴胺能（DAergic）神经元的逐渐丧失引起。这导致纹状体中多巴胺（DA）含量减少，从而影响基底神经节的精细调节。在患者中，这种失衡表现为运动不能、僵住症和震颤。与PD相关的行为功能障碍通常通过左旋多巴（LD）治疗得到缓解，左旋多巴是DA合成的前体。由于进行性神经退行性变，LD最终在PD中失去适用性。尽管DA具有细胞毒性，但尚不清楚LD治疗是否会加速PD进展。LD本身在体内不会导致神经退行性变，但先前的报告表明，当涉及与PD相关的遗传或表观遗传异常时，LD治疗介导的过量DA可增强神经毒性。因此，在治疗期间将DA毒性降至最低是阻止或减缓PD进展的绝对必要条件。与DA毒性相关的两个主要因素是：单胺氧化酶降解和DA醌（DAQ）形成。
在此，我们报告通过钙调神经磷酸酶（CaN）-动力相关蛋白1（DRP1）轴的凋亡性线粒体碎片化是这两个初始信号的共同下游事件，抑制该过程可全面保护细胞免受DA毒性。当仅阻断CaN的PxIxIT结构域时，就细胞存活而言未观察到保护作用，这表明特异性阻断DRP1-CaN轴的重要性。此外，在小鼠模型中评估DA暴露对PD进展的影响发现，LD介导的行为恢复随时间减弱，主要是因为纹状体中持续的DA能细胞死亡和树突棘丧失。单独或与LD联合使用CaN抑制剂可提供长期行为保护。这种保护作用是通过特异性阻碍CaN-DRP1轴介导的，而当联合使用LD时，抑制CaN与其他底物（包括参与神经炎症的蛋白质）之间的相互作用仍然无效。
在本研究中，我们得出结论，抑制CaN可规避DA毒性，并且通过保护纹状体中的神经元结构可减轻与PD相关的行为异常。我们提出CaN抑制剂可能会延长LD治疗的疗效。
