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.
Original language | English (US) |
---|---|
Article number | 83 |
Journal | Acta Neuropathologica Communications |
Volume | 10 |
Issue number | 1 |
DOIs | |
State | Published - Dec 2022 |
Bibliographical note
Funding Information:This work was supported by the Biomedical Research Awards for Interdisciplinary New Science BRAINS (to R.G.P) and the National Institute of Health NINDS (R01 NS110694-01A1) (to R.G.P). The Center for Magnetic Resonance Research is supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) grant P41 EB027061, the Institutional Center Cores for Advanced Neuroimaging award P30 NS076408 and the W.M. Keck Foundation. F.C. was supported by the GLOBUS Placement program. National Institute of Health NINDS (R01 NS197387) (to M.C.) and National Institute of Health NINDS R01 MH119355 and R01 NS108686 (to A.A). Grants from Fundación Ramón Areces, MICINN (SAF2009-08233) and MCIU/AEI/FEDER-UE (RTI2018-096322-B-100) to JJL.
Publisher Copyright:
© 2022, The Author(s).
Keywords
- Alpha-synuclein
- CK2 alpha prime
- Huntington’s disease
- Neuroinflammation
- Polyglutamine
- Protein aggregation
Center for Magnetic Resonance Research (CMRR) tags
- ANDI
- P41
PubMed: MeSH publication types
- Journal Article
- Research Support, Non-U.S. Gov't
- Research Support, N.I.H., Extramural