Casein Kinase 2 Mediates HIV- and Opioid-Induced Pathologic Phosphorylation of TAR DNA Binding Protein 43 in the Basal Ganglia

Abstract

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. Summary Statement 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.