Casein kinase II preferentially phosphorylates human tau isoforms containing an amino-terminal insert. Identification of threonine 39 as the primary phosphate acceptor.

Greenwood, Jeffrey A.; Scott, Clay W.; Spreen, Russell C.; Caputo, Claudia B.; Johnson, Gail V.W.

doi:10.1016/s0021-9258(17)41790-x

Cited by 80 publications

(11 citation statements)

References 55 publications

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“…CK2 is involved in the phosphorylation and aggregation of other pathological proteins like microtubule associated protein tau (MAPT) and α-syn, proteins involved in Alzheimer’s (AD) and Parkinson’s disease (PD) [ 39 , 73 ]. Phosphorylation of Tau and α-syn contribute to the activation of neuroinflammatory processes, transcriptional dysregulation, and synaptic deficits in AD and PD [ 46 , 55 ].…”

Section: Introductionmentioning

confidence: 99%

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

Zarate

White

et al. 2022

acta neuropathol commun

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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.

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Section: Introductionmentioning

confidence: 99%

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

Zarate

White

et al. 2022

acta neuropathol commun

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“…CK2 is expressed in various tissues ( Faust and Montenarh, 2000 ) and particularly highly in the mammalian brain ( Blanquet, 2000 ; Castello et al, 2017 ). Fitting to this, it was linked to neurodegenerative disorders such as Parkinson’s disease ( Ryu et al, 2008 ; Borgo et al, 2021 ) and Alzheimer’s disease ( Greenwood et al, 1994 ; Rosenberger et al, 2016 ) as well as to brain tumours like glioblastoma ( Nitta et al, 2015 ; Rowse et al, 2017 ). The Okur-Chung neurodevelopmental syndrome (OCNDS) is a recent addition to CK2-associated pathologies of the nervous system.…”

Section: Introductionmentioning

confidence: 99%

Structural and Enzymological Evidence for an Altered Substrate Specificity in Okur-Chung Neurodevelopmental Syndrome Mutant CK2αLys198Arg

Werner

Gast

Lindenblatt

et al. 2022

Front. Mol. Biosci.

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Specific de novo mutations in the CSNK2A1 gene, which encodes CK2α, the catalytic subunit of protein kinase CK2, are considered as causative for the Okur-Chung neurodevelopmental syndrome (OCNDS). OCNDS is a rare congenital disease with a high phenotypic diversity ranging from neurodevelopmental disabilities to multi-systemic problems and characteristic facial features. A frequent OCNDS mutation is the exchange of Lys198 to Arg at the center of CK2α′s P+1 loop, a key element of substrate recognition. According to preliminary data recently made available, this mutation causes a significant shift of the substrate specificity of the enzyme. We expressed the CK2αLys198Arg recombinantly and characterized it biophysically and structurally. Using isothermal titration calorimetry (ITC), fluorescence quenching and differential scanning fluorimetry (Thermofluor), we found that the mutation does not affect the interaction with CK2β, the non-catalytic CK2 subunit, and that the thermal stability of the protein is even slightly increased. However, a CK2αLys198Arg crystal structure and its comparison with wild-type structures revealed a significant shift of the anion binding site harboured by the P+1 loop. This observation supports the notion that the Lys198Arg mutation causes an alteration of substrate specificity which we underpinned here with enzymological data.

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“…CK2 is involved in the phosphorylation and aggregation of other pathological proteins like microtubule associated protein tau (MAPT) and alpha-synuclein (α-syn), proteins involved in Alzheimer’s (AD) and Parkinson’s disease (PD) (16, 17). Phosphorylation of Tau and α-syn contribute to the activation of neuroinflammatory processes, transcriptional dysregulation, and synaptic deficits in AD and PD (18, 19).…”

Section: Introductionmentioning

confidence: 99%

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

Zarate

Cuccu

et al. 2020

Preprint

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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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Casein kinase II preferentially phosphorylates human tau isoforms containing an amino-terminal insert. Identification of threonine 39 as the primary phosphate acceptor.

Cited by 80 publications

References 55 publications

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

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

Structural and Enzymological Evidence for an Altered Substrate Specificity in Okur-Chung Neurodevelopmental Syndrome Mutant CK2αLys198Arg

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

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