Reduction of protein kinase MARK4 in the brains of experimental scrapie rodents and human prion disease correlates with deposits of PrPSc

Gong,Han-Shi; Guo,Yan; Tian,Chan; Xie,Wu-Ling; Shi,Qi; Zhang,Jin; Xu,Yin; Wang,Shao-Bin; Zhang,Bao-Yun; Chen,Cao; Liu,Yong; Dong,Xiao-Ping

doi:10.3892/ijmm.2012.1025

Reduction of protein kinase MARK4 in the brains of experimental scrapie rodents and human prion disease correlates with deposits of PrPSc

Authors:
- Han-Shi Gong
- Yan Guo
- Chan Tian
- Wu-Ling Xie
- Qi Shi
- Jin Zhang
- Yin Xu
- Shao-Bin Wang
- Bao-Yun Zhang
- Cao Chen
- Yong Liu
- Xiao-Ping Dong
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Affiliations: School of Medicine, Xi'an Jiao Tong University, Xi'an 710061, P.R. China, State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, P.R. China
Published online on: June 12, 2012 https://doi.org/10.3892/ijmm.2012.1025
Pages: 569-578

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Abstract

Microtubule affinity-regulating kinase 4 (MARK4) belongs to a family of kinases that are able to actively phosphorylate the neuronal microtubule-associate proteins (MAPs), such as tau, MAP2 and the ubiquitous MAP4. Abnormal changes in tubulin and the profiles of tau have been previously reported in the human brain and animal transmissible spongiform encephalopathies (TSEs), which may be associated with abnormal alterations of various cellular kinases. To elucidate the possible role of MARK4 in TSE pathogenesis, the MARK4 levels in the brain tissues of scrapie-infected rodents and human prion diseases were evaluated using western blotting and immunohistochemical assays. The results revealed that at terminal stages of the diseases, MARK4 levels in the brain tissues of the scrapie 263K-infected hamsters, 139A-infected mice and a case of Creutzfeldt-Jakob disease (CJD, G114V gCJD) correlated with amounts of PrPSc deposits that were almost undetectable. On the other hand MARK4 signals were noticeable in the brain tissues of a fatal familial insomnia (FFI) patient without PrPSc. The reduction of MARK4 was closely related to the prolonged incubation times. These results could be reproduced in SK-N-SH and PC12 cell lines after being exposed to the synthetic peptide PrP106-126. Accordingly, the levels of phosphorylated tau at Ser262 (p-tau262) in cultured cells exposed to PrP106-126, or the ratios of p-tau262/total tau in the brain tissues of 263K-infected hamsters were also significantly decreased. According to our data there is a correlation between a TSE pathological-associated decline of MARK4 in the brain tissues with the deposits of PrPSc. Reduction of MARK4 will result in abnormalities of tau phosphorylation, and possibly induce further detachment of microtubules and hinder microtubule transportation.

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