Instituto de Investigaciones Biomédicas (CSIC-UAM), Arturo Duperier, 4, 28029, Madrid, Spain.
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Valderrebollo, 5, 28031, Madrid, Spain.
Mol Neurobiol. 2020 Feb;57(2):806-822. doi: 10.1007/s12035-019-01745-z. Epub 2019 Aug 31.
Parkinson's disease is characterized by a loss of dopaminergic neurons in the ventral midbrain. This disease is diagnosed when around 50% of these neurons have already died; consequently, therapeutic treatments start too late. Therefore, an urgent need exists to find new targets involved in the onset and progression of the disease. Phosphodiesterase 7 (PDE7) is a key enzyme involved in the degradation of intracellular levels of cyclic adenosine 3', 5'-monophosphate in different cell types; however, little is known regarding its role in neurodegenerative diseases, and specifically in Parkinson's disease. We have previously shown that chemical as well as genetic inhibition of this enzyme results in neuroprotection and anti-inflammatory activity in different models of neurodegenerative disorders, including Parkinson's disease. Here, we have used in vitro and in vivo models of Parkinson's disease to study the regulation of PDE7 protein levels. Our results show that PDE7 is upregulated after an injury both in the human dopaminergic cell line SH-SY5Y and in primary rat mesencephalic cultures and after lipopolysaccharide or 6-hidroxydopamine injection in the Substantia nigra pars compacta of adult mice. PDE7 increase takes place mainly in degenerating dopaminergic neurons and in microglia cells. This enhanced expression appears to be direct since 6-hydroxydopamine and lipopolysaccharide increase the expression of a 962-bp fragment of its promoter. Taking together, these results reveal an essential function for PDE7 in the pathways leading to neurodegeneration and inflammatory-mediated brain damage and suggest novel roles for PDE7 in neurodegenerative diseases, specifically in PD, opening the door for new therapeutic interventions.
帕金森病的特征是中脑腹侧多巴胺能神经元的丧失。当这些神经元中约有 50%已经死亡时，就会诊断出这种疾病；因此，治疗开始得太晚了。因此，迫切需要找到新的靶点来参与疾病的发生和进展。磷酸二酯酶 7（PDE7）是一种关键的酶，参与不同细胞类型中环磷酸腺苷 3'，5'-单磷酸的细胞内水平的降解；然而，关于其在神经退行性疾病中的作用，特别是在帕金森病中的作用知之甚少。我们之前已经表明，该酶的化学和遗传抑制会导致不同神经退行性疾病模型（包括帕金森病）中的神经保护和抗炎活性。在这里，我们使用了帕金森病的体外和体内模型来研究 PDE7 蛋白水平的调节。我们的结果表明，PDE7 在人多巴胺能细胞系 SH-SY5Y 和原代大鼠中脑培养物中的损伤后以及在脂多糖或 6-羟多巴胺注射到成年小鼠的黑质致密部后均上调。PDE7 的增加主要发生在退化的多巴胺能神经元和小胶质细胞中。这种增强的表达似乎是直接的，因为 6-羟多巴胺和脂多糖增加了其启动子的 962bp 片段的表达。总之，这些结果揭示了 PDE7 在导致神经退行性变和炎症介导的脑损伤的途径中的重要功能，并提示 PDE7 在神经退行性疾病（特别是 PD）中具有新的作用，为新的治疗干预措施开辟了道路。
