Department of Human Molecular Genetics, Institute of Human Genetics, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Goettingen, Goettingen, Germany.
Sci Rep. 2020 Apr 8;10(1):6064. doi: 10.1038/s41598-020-62678-5.
The neuropathological hallmarks of Parkinson's disease include preferential vulnerability of dopaminergic neurons of the substantia nigra pars compacta, and accumulation of intraneuronal protein inclusions known as Lewy bodies. These inclusions contain, among other proteins, aggregated alpha-synuclein and histone deacetylase 6 (HDAC6). In our study we found that selective inhibition of HDAC6 activity by Tubastatin A has protective effects in a rat model of Parkinson's disease. We provide evidence that this protection may be due to the activation of chaperone-mediated autophagy through the up-regulation of key members of this pathway. Moreover, Tubastatin A significantly inhibited the expression of a toxic form of alpha-synuclein that is phosphorylated at serine position 129. Tubastatin A treatment also permitted to partially modulate neuroinflammation. Taken together, our study highlights the neuroprotective effects of Tubastatin A in a rat model of Parkinson's disease and provides mechanistic insight in Tubastatin A-mediated protection against alpha-synuclein toxicity and substantia nigra degeneration. These findings are of potential therapeutic value in Parkinson's disease and other synucleinopathies.
帕金森病的神经病理学特征包括黑质致密部多巴胺能神经元的优先易损性，以及被称为路易体的细胞内蛋白包涵体的积累。这些包含物含有聚集的α-突触核蛋白和组蛋白去乙酰化酶 6（HDAC6）等蛋白。在我们的研究中，我们发现 Tubastatin A 对 HDAC6 活性的选择性抑制在帕金森病大鼠模型中具有保护作用。我们提供的证据表明，这种保护可能是由于通过上调该途径的关键成员激活伴侣介导的自噬。此外，Tubastatin A 还显著抑制了丝氨酸 129 位磷酸化的有毒形式α-突触核蛋白的表达。Tubastatin A 处理还允许部分调节神经炎症。总之，我们的研究强调了 Tubastatin A 在帕金森病大鼠模型中的神经保护作用，并提供了 Tubastatin A 介导的对α-突触核蛋白毒性和黑质变性的保护作用的机制见解。这些发现对帕金森病和其他突触核蛋白病具有潜在的治疗价值。
