Protein Kinase CK2alpha prime: A Unifying Regulator and Therapeutic Candidate in PolyQ Expansion Disorders and Tauopathies

Abstract

Protein kinase CK2 is a serine/threonine kinase widely known for its role in cancer, inflammation and cell survival. CK2 has been implicated to contribute to pathology in a wide variety of neurodegenerative disorders including polyglutamine (PolyQ) expansion disorders such as Huntington’s disease (HD) and Spinocerebellar axtaxia 3 (SCA3), as well as Parkinsons disease (PD), Alzheimer’s disease (AD), Frontotemporal dementia (FTD), and Amyotrophic lateral sclerosis (ALS). Despite this the extent and mechanism underlying CK2 mediated neurodegeneration remain poorly understood. Previous work from our lab supports a role specifically of CK2α’, one of the catalytic subunits of CK2, in HD pathology and progression. CK2α’ exhibits more restricted expression than the CK2α subunit and has a smaller number of described substrates, making it a potentially more attractive therapeutic target. In HD we have shown that heterozygous knockout of CK2α’ reduces mutant Huntingtin (mHTT) aggregation, improves motor behavior, increases synaptic density and improves synaptic function. CK2α’ haploinsufficiency also ameliorates gene dysregulation related to glutamatergic synaptic function, including genes predicted to be downstream of αSynuclein (αSyn). Notably this dissertation demonstrates that phosphorylation of αSyn at serine 129 (pS129-αSyn), which is associated with synucleinopathy and glutamatergic gene dysregulation, was decreased in HD mice haploinsufficient for CK2α’, linking CK2α’ to αSyn mediated gene dysregulation in HD. CK2 has also been heavily implicated in tauopathies, including AD and other AD related dementias (ADRD) such as FTD, which are characterized by the abnormal accumulation of phosphorylated Tau (pTau). We demonstrate a subunit specific elevation of CK2α’ in ADRD patient tissues associated with tau pathology. In addition, we have also demonstrated an elevation of CK2α’ in the PS19 mouse model of tauopathy. Genetic depletion of CK2α’ in both a N2a cell model of tauopathy and the PS19 mouse model led to a decrease in pTau. Although further analysis revealed that impacts of CK2α’ depletion in the PS19 model appeared to be operating independently of the pS129-αSyn pathways identified in HD. RNA-Seq analysis prompted us to investigate the impacts of CK2α’ haploinsufficiency on inflammatory pathways, particularly related to microglia and phagocytosis. CK2α’ haploinsufficiency in the PS19 mouse model result in decreased markers of reactive and phagocytic microglia, decreased phagocytosis of synaptic components, increase neuronal and synaptic density, and improved synaptic function. These improvements were also associated with enhanced cognitive performance in PS19 mice haploinsufficient for CK2α’. While the precise molecular mechanisms remain unclear, our data highlight several promising candidates for future investigation, including LSD1, STING1, STAT1 and IRF3. Finally, we explored pharmacological inhibition of CK2 using the FDA-designated orphan drug Silmitasertib (CX-4945) in PS19 mice and CK2α’ specific inhibitors in cell models of HTT and tau pathology. In vivo CX-4945 treatment ameliorated hyperactivity but did not impact cognitive behavior or pathological markers such as pTau and microgliosis, suggesting earlier intervention may be more effective. In vitro treatment of N2a cells overexpressing mutant Huntingtin or Tau with novel CK2α’ specific inhibitors reduced mHTT aggregation, although no effect was observed on tau phosphorylation. Further studies using more aggressive tau models are planned. Overall, this work provides substantial genetic evidence supporting a role of CK2α’ in both HD and tauopathies. Providing further support for CK2α’ as a unifying regulator and therapeutic candidate in PolyQ expansion disorders and tauopathies.