Pharmacological inhibition of CK2: the effect of an FDA designated orphan drug on pathology, neuroinflammation, and glial phenotypes in Huntington’s disease

Abstract

Huntington’s disease (HD) is a devastating autosomal dominant neurodegenerative disease that manifests with progressive motor, cognitive, and psychological impairments. HD is caused by a polyQ (CAG) repeat expansion in the huntingtin (HTT) gene, leading to the misfolding and aggregation of mutant HTT protein (mHTT) and the preferential degeneration of the striatum. Previously in our lab, we identified Protein Kinase CK2 as an important kinase involved in the pathophysiology of HD. Specifically, the alpha prime catalytic subunit of CK2 (CK2α’) is upregulated in HD, and genetic depletion of CK2α’ in HD mice results in improved motor behavior, decreased mutant Htt aggregation, and improved neuronal function. Silmitasertib (CX-4945) is an FDA designated orphan drug that inhibits CK2. This study aims to investigate whether CX-4945 treatment ameliorates HD pathology. We treated prodromal and late symptomatic HD mice, and used a variety of immunohistochemical, biochemical, physiological and behavioral approaches. We found that CX-4945 presented benefits in the amelioration of HD pathophysiology in both treated groups. Importantly, we found CX-4945 decreased mHtt aggregation, increased DARPP-32 expression and excitatory synapse density, restored homeostatic astrocyte phenotypes and ameliorated neuroinflammation and microgliosis, altogether resulting in improved motor behavior. These results support CX-4945 as a strong candidate for a targeted therapy to treat HD. Additionally, we explored the unknown role of GFAP+ astrocytes in the striatum, which cluster around white matter fascicles originating from the secondary motor cortex (M2). The M2-striatum pathway is involved in motivation and degeneration in HD can lead to apathy, one of the major psychiatric symptoms in HD. We aimed to determine the function of GFAP+ astrocytes in the striatum by removing them from the DMS using a viral mediated approach. We found that removal of GFAP+ astrocytes increased mHtt aggregation, decreased the number of medium spiny neurons (MSNs) and allowed increased infiltration of mHtt aggregates into white matter fascicles. Removal of GFAP+ astrocytes also increased the number of white matter fascicles in the DMS. Overall, these results support a neuroprotective role for GFAP+ astrocytes in the HD striatum.