Protein kinase CK2 alpha prime and alpha-synuclein constitute a key regulatory pathway in Huntington's disease

Huntingtons Disease (HD) is a neurodegenerative disorder caused by 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 (-syn), mostly associated with Parkinsons disease (PD), has recently been involved in motor deficits in HD, but its mechanism of action is unknown. Here we showed that -syn serine 129 phosphorylation (-syn-pS129), a posttranslational modification linked to -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 (CK2), which is preferentially induced in striatal neurons in HD. Knocking out one allele of CK2 in zQ175 mice decreased -syn-pS129 in the striatum and ameliorated several HD-like symptoms including neuroinflammation, transcriptional alterations, excitatory synaptic transmission deficits and motor dysfunction. Our data suggests CK2-mediated synucleinopathy as a key molecular mechanism of neurodegeneration in HD.