CK2 alpha prime and alpha-synuclein pathogenic functional interaction mediates synaptic dysregulation in Huntington's disease

Huntington’s disease (HD) is a neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in theHTT gene for which no therapies are available. HTT mutation causes protein misfolding and aggregation, preferentiallyaffecting medium spiny neurons (MSNs) of the basal ganglia. Transcriptional perturbations in synaptic genesand neuroinflammation are key processes that precede MSN dysfunction and motor symptom onset. Understandingthe interplay between these processes is crucial to develop effective therapeutic strategies to treat HD. We investigatedthe role of protein kinase CK2α’, a kinase upregulated in MSNs in HD and previously associated with Parkinson’sdisease (PD), in the regulation of neuroinflammation and synaptic function in HD. We used the heterozygous knock-inzQ175 HD mouse model and compared that to zQ175 mice lacking one allele of CK2α’ (zQ175:CK2α’(±)). CK2α’ haploinsufficiencyin zQ175 mice resulted in decreased levels of pro-inflammatory cytokines, HTT aggregation, astrogliosisand transcriptional alterations of synaptic genes related to glutamatergic signaling. zQ175:CK2α’(±) mice also presentedincreased frequency of striatal miniature excitatory postsynaptic currents (mEPSCs), an indicator of synapticactivity, and improved motor coordination compared to zQ175 mice. Neuropathological and phenotypic changesmediated by CK2α’ were connected to alpha-synuclein (α-syn) dysregulation and correlated with differences in α-synserine 129 phosphorylation (pS129-α-syn), a post-translational modification involved in α-synucleinopathy and shownto be regulated by CK2 in PD. pS129-α-syn was increased in the nuclei of MSNs in zQ175 mice and in the striatumof patients with HD, and it decreased in zQ175:CK2α’(±) mice. Collectively, our data established a novel connectionbetween CK2α’, neuroinflammation and synaptic gene dysregulation with synucleinopathy in HD and suggestedcommon molecular mechanisms of neurodegeneration between HD and PD. Our results also support CK2α’ inhibitionas a potential therapeutic strategy to modulate neuronal function and neuroprotection in HD.