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

Yu, Dahyun; Zarate, Nicole; Cuccu, Francesco; Yue, Johnny S.; Brown, Taylor G.; Tsai, Wei Tek; Mansky, Rachel H.; Jiang, Kevin; Kim, Hyuck; White, Angel; Nanclares, Carmen; Nichols-Meade, Tessa; Larson, Sarah N.; Gundry, Katie; Zhang, Ying; Tomás‐Zapico, Cristina; Lucas, José J.; Benneyworth, Michael A.; Öz, Gülin; Cvetanović, Marija; Araque, Alfonso; Gómez-Pastor, Rocío

doi:10.1101/2020.10.29.359380

Cited by 4 publications

(17 citation statements)

References 141 publications

(370 reference statements)

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“…However, this alteration most likely reflects changes in tCr. Lower NAA and higher Ins, which are considered markers of neurodegeneration, were previously reported in more severe HD mouse models such as the R6/2 (12 weeks) (Tkác et al, 2007), homozygous zQ175 (Tg/Tg) (12 months) (Peng et al, 2016) and in older zQ175 Tg/0 (22 months) (Tkác et al, 2007;Heikkinen et al, 2012;Peng et al, 2016;Yu et al, 2020). Therefore, these data suggests that tNAA and Ins may reflect substantial neurodegeneration in advanced disease.…”

Section: Longitudinal In Vivo 1 H-mrs Captures Genotype and Age-specific Striatal Neurochemical Changes In The Zq175 Hd Mouse Modelsupporting

confidence: 69%

“…Previous studies in patients with different spinocerebellar ataxias (SCAs) presenting different degrees of synapse loss proposed that neurochemical alterations measured by MRS may reflect changes in synaptic function or density (Öz et al, 2011a;Joers et al, 2018). Consistently, a recent MRS study in aged zQ175 mice showed that key striatal neurochemical alterations paralleled changes in T-S synapses (Yu et al, 2020), highlighting the potential use of MRS as a tool to monitor synapse density. However, the relationship between neurochemical alterations and synaptic density has not been directly assessed thus far.…”

Section: Introductionmentioning

confidence: 73%

“…2E), while no significant differences were observed between WT and zQ175:CK2α' (+/-) mice at the later time points, indicating that the characteristic increase in Gln in zQ175 could be delayed as a consequence of manipulating CK2α' levels. zQ175:CK2α' (+/-) mice have previously shown decreased HTT aggregation in the striatum, increased excitatory synaptic transmission and improved motor coordination compared to zQ175 (Yu et al, 2020).…”

Section: Longitudinal In Vivo 1 H-mrs Captures Genotype and Age-specific Striatal Neurochemical Changes In The Zq175 Hd Mouse Modelmentioning

confidence: 97%

“…Given the previously described positive effects of CK2α' haploinsufficiency in ameliorating HD-like symptoms (Gomez-Pastor et al, 2017;Yu et al, 2020), we expected to see a number of neurochemicals that were significantly different between zQ175 and zQ175:CK2α' (+/-) mice. Interestingly, we only observed significant differences between these two genotypes at 3 months for Gln (Fig.…”

Section: Longitudinal In Vivo 1 H-mrs Captures Genotype and Age-specific Striatal Neurochemical Changes In The Zq175 Hd Mouse Modelmentioning

confidence: 99%

“…In the present study we conducted in vivo longitudinal high field proton ( 1 H) MRS in the striatum of the heterozygous zQ175 HD mouse model followed by ex-vivo analyses of excitatory synapse densities of two major, differentially altered striatal synaptic circuits in HD; cortico-striatal (C-S) and thalamo-striatal (T-S). We also studied zQ175 mice lacking one allele of CK2α', a kinase involved in synapse stability in HD, the haploinsufficiency of which differentially altered T-S and C-S circuitry and ameliorated long-term HD-like symptoms (Gomez-Pastor et al, 2017;Yu et al, 2020). We found that T-S synaptic density was significantly correlated with alterations in alanine (Ala), lactate (Lac), phosphoethanolamine (PE), and total creatine (tCr) while C-S synapse number significantly correlated with gamma-aminobutyric acid (GABA).…”

Section: Introductionmentioning

confidence: 99%

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In vivo MR spectroscopy reflects synapse density in a Huntington’s disease mouse model

Zarate

Gundry

et al. 2021

Preprint

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BackgroundStriatal medium spiny neurons are highly susceptible in Huntington’s disease (HD), resulting in early synaptic perturbations that lead to neuronal dysfunction and death. Non-invasive imaging techniques, such as proton magnetic resonance spectroscopy (1H-MRS), have been used in HD mouse models and patients with HD to monitor neurochemical changes associated with neuronal health. However, the molecular connection between brain neurochemical alterations and synaptic dysregulation is unknown, limiting our ability to monitor potential treatments that may affect synapse function.ObjectiveAssess the intersection of synapse density and 1H-MRS during disease progression in an HD mouse model.MethodsWe conducted in vivo longitudinal 1H-MRS in the striatum followed by ex-vivo analyses of excitatory synapse density of two synaptic circuits disrupted in HD: thalamo-striatal (T-S) and cortico-striatal (C-S) pathways. We used the heterozygous knock-in zQ175 HD mouse model as well as zQ175 mice lacking one allele of CK2α’(zQ175(Tg/0):CK2α’(+/-)), a kinase previously shown to regulate synapse function in HD.ResultsLongitudinal analyses of excitatory synapse density showed early and sustained reduction in T-S synapses in zQ175 mice, preceding C-S synapse depletion, which was rescued in zQ175:CK2α’(+/-). Linear regression analyses showed C-S synapse number correlated with 1H-MRS-measured levels of GABA while T-S synapse number positively correlated with alterations in the levels of alanine, phosphoethanolamine, lactate, and taurine relative to total creatine.ConclusionWe propose these neurochemicals could be used as surrogate biomarkers to monitor circuit-specific synaptic dysfunction using 1H-MRS in the zQ175 mouse model and perhaps in HD pre-clinical studies.

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Section: Longitudinal In Vivo 1 H-mrs Captures Genotype and Age-specific Striatal Neurochemical Changes In The Zq175 Hd Mouse Modelsupporting

confidence: 69%

Section: Introductionmentioning

confidence: 73%

Section: Longitudinal In Vivo 1 H-mrs Captures Genotype and Age-specific Striatal Neurochemical Changes In The Zq175 Hd Mouse Modelmentioning

confidence: 97%

Section: Longitudinal In Vivo 1 H-mrs Captures Genotype and Age-specific Striatal Neurochemical Changes In The Zq175 Hd Mouse Modelmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In vivo MR spectroscopy reflects synapse density in a Huntington’s disease mouse model

Zarate

Gundry

et al. 2021

Preprint

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Striatal compartmentalization and clustering of different subtypes of astrocytes is altered in the zQ175 Huntington’s disease mouse model

Brown

Thayer

Zarate

et al. 2021

Preprint

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Huntington’s disease (HD) is a devastating neurodegenerative disease that primarily affects the striatum, a brain region that controls movement and some forms of cognition. Dysfunction and loss of medium spiny neurons of the striatum is accompanied by astrogliosis (increased astrocyte density and pathology). For decades, astrocytes were considered a homogeneous cell type, but recent transcriptomic analyses revealed astrocytes are a heterogeneous population classified into multiple subtypes depending on the expression of different gene markers. Here, we studied whether three different striatal astrocyte subtypes expressing glutamine synthetase (GS), glial fibrillary acidic protein (GFAP), or S100 calcium-binding protein B (S100B) are differentially altered in HD. We conducted a comparative immunofluorescence analysis in the striatum of WT and the heterozygous zQ175 HD mouse model and found that the expression and abundance of GFAP+ and S100B+ astrocytes increased in zQ175 mice, while GS+ astrocytes showed no alteration. We then explored whether there was a differential spatial distribution of any of these subtypes within the striatum. We developed a systematic brain compartmentalization approach and found that while GS+ and S100B+ astrocytes were more homogeneously distributed throughout the striatum in zQ175 mice, GFAP+ astrocytes preferentially accumulated in the dorsomedial and dorsolateral striatum, which are regions associated with goal-directed and habitual behaviors. Additionally, GFAP+ astrocytes in zQ175 mice showed increased clustering, a parameter that indicates increased proximity and that is associated with localized inflammation and/or neurodegeneration. Our data suggest a differential susceptibility in both increased density and striatal compartmentalization of different subtypes of astrocytes in zQ175. These results highlight new potential implications for our understanding of astrocyte pathology in HD.

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Striatal spatial heterogeneity, clustering, and white matter association of GFAP+ astrocytes in a mouse model of Huntington’s disease

Brown¹,

Thayer²,

VanTreeck³

et al. 2023

Front. Cell. Neurosci.

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IntroductionHuntington’s disease (HD) is a neurodegenerative disease that primarily affects the striatum, a brain region that controls movement and some forms of cognition. Neuronal dysfunction and loss in HD is accompanied by increased astrocyte density and astrocyte pathology. Astrocytes are a heterogeneous population classified into multiple subtypes depending on the expression of different gene markers. Studying whether mutant Huntingtin (HTT) alters specific subtypes of astrocytes is necessary to understand their relative contribution to HD.MethodsHere, we studied whether astrocytes expressing two different markers; glial fibrillary acidic protein (GFAP), associated with astrocyte activation, and S100 calcium-binding protein B (S100B), a marker of matured astrocytes and inflammation, were differentially altered in HD.ResultsFirst, we found three distinct populations in the striatum of WT and symptomatic zQ175 mice: GFAP+, S100B+, and dual GFAP+S100B+. The number of GFAP+ and S100B+ astrocytes throughout the striatum was increased in HD mice compared to WT, coinciding with an increase in HTT aggregation. Overlap between GFAP and S100B staining was expected, but dual GFAP+S100B+ astrocytes only accounted for less than 10% of all tested astrocytes and the number of GFAP+S100B+ astrocytes did not differ between WT and HD, suggesting that GFAP+ astrocytes and S100B+ astrocytes are distinct types of astrocytes. Interestingly, a spatial characterization of these astrocyte subtypes in HD mice showed that while S100B+ were homogeneously distributed throughout the striatum, GFAP+ preferentially accumulated in “patches” in the dorsomedial (dm) striatum, a region associated with goal-directed behaviors. In addition, GFAP+ astrocytes in the dm striatum of zQ175 mice showed increased clustering and association with white matter fascicles and were preferentially located in areas with low HTT aggregate load.DiscussionIn summary, we showed that GFAP+ and S100B+ astrocyte subtypes are distinctly affected in HD and exist in distinct spatial arrangements that may offer new insights to the function of these specific astrocytes subtypes and their potential implications in HD pathology.

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

Cited by 4 publications

References 141 publications

In vivo MR spectroscopy reflects synapse density in a Huntington’s disease mouse model

In vivo MR spectroscopy reflects synapse density in a Huntington’s disease mouse model

Striatal compartmentalization and clustering of different subtypes of astrocytes is altered in the zQ175 Huntington’s disease mouse model

Striatal spatial heterogeneity, clustering, and white matter association of GFAP+ astrocytes in a mouse model of Huntington’s disease

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