CK2 alpha prime and alpha-synuclein pathogenic functional interaction mediates inflammation and transcriptional dysregulation in Huntington’s disease

Huntington’s Disease (HD) is a neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the Htt gene for which no therapies are available. This mutation causes HTT protein misfolding and aggregation, preferentially affecting medium spiny neurons (MSNs) of the basal ganglia. Transcriptional perturbations in synaptic genes and neuroinflammation are key processes that precede MSN dysfunction and motor symptom onset. Understanding the interplay between these processes is crucial to develop effective therapeutic strategies to treat HD. We investigated whether protein kinase CK2α’, a kinase upregulated in MSNs in HD and previously associated with Parkinson’s disease (PD), participates in the regulation of neuroinflammation and synaptic function during HD progression. We used the heterozygous knock-in zQ175 HD mouse model that lacks one allele of CK2α’ and performed cytokine proteome profiling, RNA-seq, electrophysiological recordings, and behavioral analyses. We showed that CK2α’ haploinsufficiency in zQ175 mice ameliorated neuroinflammation, HTT aggregation, transcriptional alterations, excitatory synaptic transmission deficits, and motor dysfunction. Our RNA-seq analyses also revealed a connection between α-syn, a protein associated with PD, and the transcriptional perturbations mediated by CK2α’ in HD. We found that CK2α’ increased α-syn serine 129 phosphorylation (pS129-α-syn), a post-translational modification linked to α-synucleinopathy, and its accumulation in the nucleus of MSNs in zQ175 mice and in patients with HD. Our data demonstrated that CK2α’ negatively contributes to HD by promoting striatal synucleinopathy, transcriptional alteration of synaptic genes and neuroinflammation. We propose CK2α’ as a potential therapeutic target to treat HD. Significance statement Upregulation of Protein kinase CK2α’ mediates neuroinflammation and transcriptional dysregulation of synaptic genes in the zQ175 mouse model of HD and its depletion improved several HD-like phenotypes in this mouse model. These effects are mediated, at least in part, by the CK2α’-dependent phosphorylation of α-syn serine 129 in the striatum of HD mice, a post-translational modification associated with synucleinopathy and PD. Our study highlights a potential convergent mechanism of neurodegeneration between HD and PD and suggests targeting CK2α’ as a therapeutic strategy to ameliorate neuroinflammation and synaptic dysfunction in HD and perhaps other neurodegenerative diseases. ### Competing Interest Statement The authors have declared no competing interest.