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

Abstract

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.

Kinases and Their Potential as Therapeutic Targets in Huntington’s Disease

“…CK2 is a serine/threonine protein kinase extensively studied in the context of cancer and inflammation [136,137] and it was first identified in relation to HD in studies using HEK293T cells co-expressing NMDA receptors (NR1 and NR2B) and human HTT-138Q where CK2 was seen to be upregulated [132]. This observation has since been validated in multiple HD models including striatal tissues from YAC72, YAC128, and zQ175 mice, in primary neurons from YAC mice, in immortalized STHdh Q111 cells, and in striatal tissues from patients with HD [132,138,139]. The study by Fan et al showed that pharmacological inhibition of CK2 exacerbated NMDA-mediated toxicity in YAC-derived neurons and proposed a protective role of CK2 in HD.…”

“…Recent studies in STHdh-Q111 cells using siRNA against different CK2 subunits showed that silencing the catalytic subunit CK2α', but not CK2α or CK2β, improved cellular toxicity [138]. Similarly, CK2α' genetic haploinsufficiency in zQ175 mice (zQ175:CK2α' (+/-) ) provided ample benefits in ameliorating several HD-like phenotypes suggesting that CK2α' plays a detrimental role in HD [138,139]. Unfortunately, these studies did not explore whether the benefits exerted by CK2α' in these various HD models had an impact on HTT phosphorylation.…”

“…A differential abundance between CK2 subunits in HD was first reported in YAC72 and YAC128 striatal tissues although their differential contribution to HD remained unknown [132]. Almost a decade later Gomez-Pastor et al showed that CK2α', but not CK2α or CK2, was specifically induced in HD cells and mouse models and in patients with HD, and that such induction played a detrimental role in HD [138,139]. Although, whether CK2α' plays a direct role in HTT phosphorylation still remains elusive, other roles for this kinase have been recently discovered in the context of HD.…”

Correction to: CK2 alpha prime and alpha-synuclein pathogenic functional interaction mediates synaptic dysregulation in Huntington’s disease

“…Following publication of the original article [ 1 ], an error was identified in the corresponding authorship and equal contributions in the author group due to a typesetting mistake: the third author, Angel White, should have been indicated as equal contributor, instead of as corresponding author.…”

“…The author group has been updated above and the original article [ 1 ] has been corrected. The publisher apologises to the authors and readers for the inconvenience caused by the error.…”