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 the HTT gene for which no therapies are available. HTT mutation causes 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 the role of protein kinase CK2 alpha', a kinase upregulated in MSNs in HD and previously associated with Parkinson's disease (PD), in the regulation of neuroinflammation and synaptic function in HD. We used the heterozygous knock-in zQ175 HD mouse model and compared that to zQ175 mice lacking one allele of CK2 alpha' (zQ175:CK2 alpha'((+/-))). CK2 alpha' haploinsufficiency in zQ175 mice resulted in decreased levels of pro-inflammatory cytokines, HTT aggregation, astrogliosis and transcriptional alterations of synaptic genes related to glutamatergic signaling. zQ175:CK2 alpha'((+/-)) mice also presented increased frequency of striatal miniature excitatory postsynaptic currents (mEPSCs), an indicator of synaptic activity, and improved motor coordination compared to zQ175 mice. Neuropathological and phenotypic changes mediated by CK2 alpha' were connected to alpha-synuclein (alpha-syn) dysregulation and correlated with differences in alpha-syn serine 129 phosphorylation (pS129-alpha-syn), a post-translational modification involved in alpha-synucleinopathy and shown to be regulated by CK2 in PD. pS129-alpha-syn was increased in the nuclei of MSNs in zQ175 mice and in the striatum of patients with HD, and it decreased in zQ175:CK2 alpha'((+/-)) mice. Collectively, our data established a novel connection between CK2 alpha', neuroinflammation and synaptic gene dysregulation with synucleinopathy in HD and suggested common molecular mechanisms of neurodegeneration between HD and PD. Our results also support CK2 alpha' inhibition as a potential therapeutic strategy to modulate neuronal function and neuroprotection in HD.

Automated summary

This study investigated the role of protein kinase CK2 alpha' in the regulation of neuroinflammation and synaptic function in Huntington's disease. The results showed that CK2 alpha' haploinsufficiency can decrease pro-inflammatory cytokines, improve synaptic activity, and enhance motor coordination in a mouse model of Huntington's disease. These findings provide important clues for developing effective therapeutic strategies for Huntington's disease.