Casein Kinase 2 Mediates HIV- and Opioid-Induced Pathologic Phosphorylation of TAR DNA Binding Protein 43 in the Basal Ganglia.
Casein Kinase 2 Mediates HIV- and Opioid-Induced Pathologic Phosphorylation of TAR DNA Binding Protein 43 in the Basal Ganglia.
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DOI：
10.1177/17590914231158218
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发表时间：
2023-01
期刊：
影响因子：
4.7
通讯作者：
Hauser, Kurt F.
中科院分区：
文献类型：
--
作者：
Ohene-Nyako, Michael;Nass, Sara R.;Richard, Hope T.;Lukande, Robert;Nicol, Melanie R.;McRae, MaryPeace;Knapp, Pamela E.;Hauser, Kurt F.
关键词：
反式激活反应(TAR)元件DNA结合蛋白43(TDP-43)的异常磷酸化和随后聚集是多种神经退行性疾病的共同特征，并与疾病的严重程度有关。在这里，我们调查了TDP-43(pTDP-43)的病理性磷酸化是否是人类免疫缺陷病毒(HIV)感染脑的一个标志。我们评估了HIV感染(HIV + )和血清阴性的死后脑标本中pTDP-43的免疫反应性和TDP-43激酶的表达。然后，我们使用了HIV-1蛋白TAT和原代神经元培养的可诱导转基因小鼠模型，以破译蛋白质病的潜在机制。由于阿片使用障碍(OUD)可以夸大HIV神经病理，我们探索了HIV-1 TAT和吗啡之间的相互作用，吗啡是一种典型的阿片类药物，对于所有结果指标。与血清阴性对照相比，死后HIV阳性的人组织 基底节神经元胞浆内pTDP-43和TdP-43免疫反应增强。对Tdp-43激酶的评估显示，在HIV阳性的 人类组织中，细胞质酪蛋白激酶2(CK2)的水平增加，但CK1δ的水平没有增加。PTDP-43与CK2水平呈显著正相关。8周的TAT诱导和2周的皮下吗啡暴露(10-40 mg/kg，增加10 mg/kg/b.i.d)。在小鼠纹状体内胞浆pTDP-43和CK2水平上独立产生了类似的结果。在原代培养的小鼠纹状体神经元中，TAT和吗啡联合作用24 h可增加pTDP-43水平和CK2活性。与CK2拮抗剂CX-4945联合治疗可阻止TAT和吗啡诱导的pTDP-43水平的升高。我们的结果表明，CK2可能是治疗神经HIV和OUD中pTDP-43蛋白病的一个可行的治疗靶点。HIV/HIV-1、TAT和吗啡单独增加纹状体TAR DNA结合蛋白43的病理性磷酸化。HIV和阿片类药物诱导的TAR DNA结合蛋白43的病理性磷酸化可能涉及CK2活性和蛋白水平的增强。
Aberrant phosphorylation and subsequent aggregation of the trans-activation response (TAR) element DNA binding protein 43 (TDP-43) is a common feature of multiple neurodegenerative disorders and contributes to disease severity. Here, we investigated whether pathologic phosphorylation of TDP-43 (pTDP-43) is a hallmark of human immunodeficiency virus (HIV)- infected brains. We evaluated pTDP-43 immunoreactivity and TDP-43 kinases in HIV-infected (HIV + ) and seronegative post-mortem brain samples. We then used an inducible transgenic mouse model of the HIV-1 protein Tat and primary neuronal cultures, to decipher the underlying mechanism of the proteinopathy. Since opioid use disorder (OUD) can exaggerate HIV neuropathology, we explored interactions between HIV-1 Tat and morphine, a prototypical opioid, for all outcome measures. Cytoplasmic pTDP-43 and TDP-43 immunoreactivities were increased in neurons of the basal ganglia of post-mortem, HIV+ human tissues compared to seronegative controls. An evaluation of TDP-43 kinases revealed an increase in the levels of cytoplasmic casein kinase 2 (CK2) in HIV-positive human tissues but not CK1δ. There was a significant positive correlation between pTDP-43 and CK2 levels. Eight weeks of Tat induction and 2-week subcutaneous morphine exposure (10–40 mg/kg, increasing by 10 mg/kg/b.i.d.) independently produced similar outcomes for cytoplasmic pTDP-43 and CK2 levels in the mouse striatum. In primary, mouse striatal neuronal cultures, co-exposure to Tat and morphine for 24 h increased pTDP-43 levels and CK2 activity. Co-treatment with the CK2 antagonist CX-4945 prevented the Tat- and morphine-induced increases in pTDP-43 levels. Our results demonstrate that CK2 may be a viable therapeutic target for treating pTDP-43 proteinopathy in neuroHIV and OUD. HIV/HIV-1 Tat and morphine independently increase pathologic phosphorylation of TAR DNA binding protein 43 in the striatum. HIV- and opioid-induced pathologic phosphorylation of TAR DNA binding protein 43 may involve enhanced CK2 activity and protein levels.
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