RT Journal Article SR Electronic T1 CK2 alpha prime and alpha-synuclein pathogenic functional interaction mediates synaptic dysregulation in Huntington’s disease JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.10.29.359380 DO 10.1101/2020.10.29.359380 A1 Dahyun Yu A1 Nicole Zarate A1 Angel White A1 De’jah Coates A1 Wei Tsai A1 Carmen Nanclares A1 Francesco Cuccu A1 Johnny S. Yue A1 Taylor G. Brown A1 Rachel Mansky A1 Kevin Jiang A1 Hyuck Kim A1 Tessa Nichols-Meade A1 Sarah N. Larson A1 Katie Gundry A1 Ying Zhang A1 Cristina Tomas-Zapico A1 Jose J. Lucas A1 Michael Benneyworth A1 Gülin Öz A1 Marija Cvetanovic A1 Alfonso Araque A1 Rocio Gomez-Pastor YR 2022 UL http://biorxiv.org/content/early/2022/01/27/2020.10.29.359380.abstract AB Background 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.Methods We used the heterozygous knock-in zQ175 HD mouse model and compared that to zQ175 mice lacking one allele of CK2α’. We performed neuropathological analyses using immunohistochemistry, cytokine proteome profiling, RNA-seq analyses in the striatum, electrophysiological recordings, and behavioral analyses. We also used the murine immortalized striatal cell lines STHdhQ7 and STHdhQ111 and studied the expression of various synaptic genes dysregulated by CK2α’.Results We showed that CK2α’ haploinsufficiency in zQ175 mice ameliorated neuroinflammation, HTT aggregation, transcriptional alterations, excitatory synaptic transmission, and motor coordination deficits. 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 also found increased α-syn serine 129 phosphorylation (pS129-α-syn), a post-translational modification linked to α-synucleinopathy, in the nuclei of MSNs in zQ175 mice and in patients with HD. Levels of pS129-α-syn were ameliorated in zQ175 lacking one allele of CK2α’.Conclusions Our data demonstrated that CK2α’ contributes to transcriptional dysregulation of synaptic genes and neuroinflammation in zQ175 mice and its depletion improved several HD-like phenotypes in this mouse model. These effects were related to increased phosphorylation of S129-α-syn in the striatum of HD mice, suggesting that CK2α’ contributes to worsening HD by mediating synucleinopathy. Our study highlights a possible convergent mechanism of neurodegeneration between HD and PD and suggests targeting CK2α’ as a potential therapeutic strategy to ameliorate synaptic dysfunction in HD as well as other neurodegenerative diseases.Competing Interest StatementThe authors have declared no competing interest.