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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >Long-term oral kinetin does not protect against α-synuclein-induced neurodegeneration in rodent models of Parkinson's disease
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Long-term oral kinetin does not protect against α-synuclein-induced neurodegeneration in rodent models of Parkinson's disease

机译：长期口腔运动蛋白不保护帕金森病啮齿动物模型中的α-突触核蛋白诱导的神经变性

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Abstract Mutations in the mitochondrial kinase PTEN-induced putative kinase 1 (PINK1) cause Parkinson's disease (PD), likely by disrupting PINK1's kinase activity. Although the mechanism(s) underlying how this loss of activity causes degeneration remains unclear, increasing PINK1 activity may therapeutically benefit some forms of PD. However, we must first learn whether restoring PINK1 function prevents degeneration in patients harboring PINK1 mutations, or whether boosting PINK1 function can offer protection in more common causes of PD. To test these hypotheses in preclinical rodent models of PD, we used kinetin triphosphate, a small-molecule that activates both wild-type and mutant forms of PINK1, which affects mitochondrial function and protects neural cells in culture. We chronically fed kinetin, the precursor of kinetin triphosphate, to PINK1-null rats in which PINK1 was reintroduced into their midbrain, and also to rodent models overexpressing α-synuclein. The highest tolerated dose of oral kinetin increased brain levels of kinetin for up to 6 months, without adversely affecting the survival of nigrostriatal dopamine neurons. However, there was no degeneration of midbrain dopamine neurons lacking PINK1, which precluded an assessment of neuroprotection and raised questions about the robustness of the PINK1 KO rat model of PD. In two rodent models of α-synuclein-induced toxicity, boosting PINK1 activity with oral kinetin provided no protective effects. Our results suggest that oral kinetin is unlikely to protect against α-synuclein toxicity, and thus fail to provide evidence that kinetin will protect in sporadic models of PD. Kinetin may protect in cases of PINK1 deficiency, but this possibility requires a more robust PINK1 KO model that can be validated by proof-of-principle genetic correction in adult animals. Highlights ? PINK1 is a mitochondrial kinase genetically linked to Parkinson’s disease. ? Kinetin is the precursor to kinetin triphosphate, a known activator of PINK1. ? Kinetin was delivered orally to three rodent models of Parkinson’s disease. ? Long-term kinetin did not protect against α-synuclein-induced neurodegeneration. ? PINK1 knockout rats did not show signs of neurodegeneration as previously reported.
机译：抽象在线粒体激酶PTEN诱导推定激酶1（PINK1）的突变导致帕金森病（PD），可能是破坏Pink1的激酶活性。虽然基础的机制是如何这种活性丧失的原因导致变性仍然不清楚，但增加粉红色的活性可能会对某种形式的Pd进行治疗。然而，我们必须首先了解恢复粉红色1功能是否可防止患者患有Pink1突变的患者的退化，或者是否促进PINK1功能可以在更常见的PD的原因提供保护。为了在Pd的临床前啮齿动物模型中测试这些假设，我们使用了激活粉红色1的野生型和突变形式的小分子的动素三磷酸，这影响线粒体功能并保护培养中的神经细胞。我们慢慢地喂养了Kinetin，三磷酸素的前体，以粉红色1重新掺入它们的中脑中的粉红色1 - 空鼠，以及过表达α-突触核蛋白的啮齿动物模型。最高耐受剂量的口腔运动蛋白增加了脑水平，长达6个月，而不会对纽格洛里亚多巴胺神经元的存活产生不利影响。然而，中脑多巴胺神经元没有缺乏粉红色的退化，这绝排不能评估神经保护，并提出了关于PD的PINK1 KO大鼠模型的鲁棒性的问题。在α-突触核蛋白诱导的毒性的两个啮齿动物模型中，用口腔运动蛋白提高PINK1活性，不提供保护作用。我们的研究结果表明，口腔运动蛋白不太可能防止α-突触核蛋白毒性，因此未能提供Kinetin将在Pd的散发模型中保护的证据。 Kinetin可以在Pink1缺乏的情况下保护，但这种可能性需要更强大的Pink1 KO模型，可以通过成年动物的原则上的原则上遗传校正来验证。强调 ？ Pink1是一种线粒体激酶遗传与帕金森病的遗传相关。还Kinetin是Kinetin三磷酸的前体，是粉红色的已知活化剂。还Kinetin以口服递送至帕金森病的三种啮齿动物模型。还长期运动蛋白未防止α-突触核蛋白诱导的神经变性。还如前所述，Pink1敲除大鼠没有显示神经变性的迹象。

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