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 CK2α’, 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 CK2α’ (zQ175:CK2α’(±)). CK2α’ 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:CK2α’(±) 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 CK2α’ were connected to alpha-synuclein (α-syn) dysregulation and correlated with differences in α-syn serine 129 phosphorylation (pS129-α-syn), a post-translational modification involved in α-synucleinopathy and shown to be regulated by CK2 in PD. pS129-α-syn was increased in the nuclei of MSNs in zQ175 mice and in the striatum of patients with HD, and it decreased in zQ175:CK2α’(±) mice. Collectively, our data established a novel connection between CK2α’, neuroinflammation and synaptic gene dysregulation with synucleinopathy in HD and suggested common molecular mechanisms of neurodegeneration between HD and PD. Our results also support CK2α’ inhibition as a potential therapeutic strategy to modulate neuronal function and neuroprotection in HD.
Huntington′s Disease (HD) is a neurodegenerative disorder caused a polyglutamine expansion in the HTT protein. This mutation causes HTT misfolding and aggregation, preferentially affecting neurons of the basal ganglia. Other aggregation-prone proteins like alpha-synuclein (α-syn), mostly associated with Parkinson′s disease (PD), has recently been involved in motor deficits in HD, but its mechanism of action is unknown. Here we showed that α-syn serine 129 phosphorylation (α-syn-pS129), a posttranslational modification linked to α-synucleinopathy, is highly phosphorylated in the brain of symptomatic zQ175 HD mice. We demonstrated that such phosphorylation is mediated by Protein Kinase CK2 alpha prime (CK2α′), which is preferentially induced in striatal neurons in HD. Knocking out one allele of CK2α′ in zQ175 mice decreased α-syn-pS129 in the striatum and ameliorated several HD-like symptoms including neuroinflammation, transcriptional alterations, excitatory synaptic transmission dysfunction and motor deficits. Our data suggests CK2α′-mediated synucleinopathy as a key molecular mechanism for striatal neurons degeneration in HD.
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