RT Journal Article
SR Electronic
T1 Protein kinase CK2 alpha prime and alpha-synuclein constitute a key regulatory pathway in Huntington’s disease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.10.29.359380
DO 10.1101/2020.10.29.359380
A1 Yu, Dahyun
A1 Zarate, Nicole
A1 Cuccu, Francesco
A1 Yue, Johnny S.
A1 Brown, Taylor G.
A1 Tsai, Adelyn
A1 Mansky, Rachel
A1 Jiang, Kevin
A1 Kim, Hyuck
A1 Nanclares, Carmen
A1 Nichols-Meade, Tessa
A1 Larson, Sarah N.
A1 Gundry, Katie
A1 Zhang, Ying
A1 Benneyworth, Michael
A1 Öz, Gülin
A1 Cvetanovic, Marija
A1 Araque, Alfonso
A1 Gomez-Pastor, Rocio
YR 2020
UL http://biorxiv.org/content/early/2020/10/29/2020.10.29.359380.abstract
AB 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 StatementThe authors have declared no competing interest.