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Protein kinase CK2 alpha prime and alpha-synuclein constitute a key regulatory pathway in Huntington’s disease

Dahyun Yu, View ORCID ProfileNicole Zarate, View ORCID ProfileFrancesco Cuccu, Johnny S. Yue, View ORCID ProfileTaylor G. Brown, View ORCID ProfileAdelyn Tsai, View ORCID ProfileRachel Mansky, Kevin Jiang, Hyuck Kim, View ORCID ProfileCarmen Nanclares, View ORCID ProfileTessa Nichols-Meade, View ORCID ProfileSarah N. Larson, Katie Gundry, View ORCID ProfileYing Zhang, View ORCID ProfileMichael Benneyworth, View ORCID ProfileGülin Öz, View ORCID ProfileMarija Cvetanovic, View ORCID ProfileAlfonso Araque, View ORCID ProfileRocio Gomez-Pastor
doi: https://doi.org/10.1101/2020.10.29.359380
Dahyun Yu
1Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, United States
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Nicole Zarate
1Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, United States
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  • ORCID record for Nicole Zarate
Francesco Cuccu
1Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, United States
3Department of Life and Environment Sciences, University of Cagliari, Cagliari, Italy
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Johnny S. Yue
1Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, United States
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Taylor G. Brown
1Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, United States
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Adelyn Tsai
1Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, United States
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Rachel Mansky
1Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, United States
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Kevin Jiang
1Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, United States
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Hyuck Kim
1Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, United States
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Carmen Nanclares
1Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, United States
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Tessa Nichols-Meade
1Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, United States
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Sarah N. Larson
2Center for Magnetic Resonance Research. Department of Radiology, School of Medicine, University of Minnesota, Minneapolis, MN, United States
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Katie Gundry
2Center for Magnetic Resonance Research. Department of Radiology, School of Medicine, University of Minnesota, Minneapolis, MN, United States
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Ying Zhang
4Minnesota supercomputing Institute, University of Minnesota. Minneapolis, MN, United States
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Michael Benneyworth
1Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, United States
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Gülin Öz
2Center for Magnetic Resonance Research. Department of Radiology, School of Medicine, University of Minnesota, Minneapolis, MN, United States
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Marija Cvetanovic
1Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, United States
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Alfonso Araque
1Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, United States
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Rocio Gomez-Pastor
1Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, United States
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  • ORCID record for Rocio Gomez-Pastor
  • For correspondence: rgomezpa@umn.edu
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Summary

Huntington’s Disease (HD) is a neurodegenerative disorder caused by 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 deficits and motor dysfunction. Our data suggests CK2α’-mediated synucleinopathy as a key molecular mechanism of neurodegeneration in HD.

Competing Interest Statement

The authors have declared no competing interest.

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Protein kinase CK2 alpha prime and alpha-synuclein constitute a key regulatory pathway in Huntington’s disease
Dahyun Yu, Nicole Zarate, Francesco Cuccu, Johnny S. Yue, Taylor G. Brown, Adelyn Tsai, Rachel Mansky, Kevin Jiang, Hyuck Kim, Carmen Nanclares, Tessa Nichols-Meade, Sarah N. Larson, Katie Gundry, Ying Zhang, Michael Benneyworth, Gülin Öz, Marija Cvetanovic, Alfonso Araque, Rocio Gomez-Pastor
bioRxiv 2020.10.29.359380; doi: https://doi.org/10.1101/2020.10.29.359380
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Protein kinase CK2 alpha prime and alpha-synuclein constitute a key regulatory pathway in Huntington’s disease
Dahyun Yu, Nicole Zarate, Francesco Cuccu, Johnny S. Yue, Taylor G. Brown, Adelyn Tsai, Rachel Mansky, Kevin Jiang, Hyuck Kim, Carmen Nanclares, Tessa Nichols-Meade, Sarah N. Larson, Katie Gundry, Ying Zhang, Michael Benneyworth, Gülin Öz, Marija Cvetanovic, Alfonso Araque, Rocio Gomez-Pastor
bioRxiv 2020.10.29.359380; doi: https://doi.org/10.1101/2020.10.29.359380

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