RRC ID 56660
著者 Saito T, Oba T, Shimizu S, Asada A, Iijima KM, Ando K.
タイトル Cdk5 increases MARK4 activity and augments pathological tau accumulation and toxicity through tau phosphorylation at Ser262.
ジャーナル Hum Mol Genet
Abstract Hyperphosphorylation of the microtubule-associated protein tau is associated with many neurodegenerative diseases, including Alzheimer's disease. Microtubule affinity-regulating kinases (MARK) 1-4 and cyclin-dependent kinase 5 (Cdk5) are tau kinases under physiological and pathological conditions. However, their functional relationship remains elusive. Here, we report a novel mechanism by which Cdk5 activates MARK4 and augments tau phosphorylation, accumulation and toxicity. MARK4 is highly phosphorylated at multiple sites in the brain and in cultured neurons, and inhibition of Cdk5 activity reduces phosphorylation levels of MARK4. MARK4 is known to be activated by phosphorylation at its activation loop by liver kinase B1 (LKB1). In contrast, Cdk5 increased phosphorylation of MARK4 in the spacer domain, but not in the activation loop, and enhanced its kinase activity, suggesting a novel mechanism by which Cdk5 regulates MARK4 activity. We also demonstrated that co-expression of Cdk5 and MARK4 in mammalian cultured cells significantly increased the levels of tau phosphorylation at both Cdk5 target sites (SP/TP sites) and MARK target sites (Ser262), as well as the levels of total tau. Furthermore, using a Drosophila model of tau toxicity, we demonstrated that Cdk5 promoted tau accumulation and tau-induced neurodegeneration via increasing tau phosphorylation levels at Ser262 by a fly ortholog of MARK, Par-1. This study suggests a novel mechanism by which Cdk5 and MARK4 synergistically increase tau phosphorylation and accumulation, consequently promoting neurodegeneration in disease pathogenesis.
巻・号 28(18)
ページ 3062-3071
公開日 2019-9-15
DOI 10.1093/hmg/ddz120
PII 5512547
PMID 31174206
MeSH Alzheimer Disease / etiology Alzheimer Disease / metabolism Alzheimer Disease / pathology Animals Axons / metabolism Brain / metabolism Brain / pathology Cyclin-Dependent Kinase 5 / metabolism* Disease Models, Animal Drosophila Gene Expression Humans Models, Biological Neurodegenerative Diseases / etiology Neurodegenerative Diseases / metabolism Neurodegenerative Diseases / pathology Neurons / metabolism Phosphorylation Protein Aggregates Protein Aggregation, Pathological* Protein Binding Protein Serine-Threonine Kinases / metabolism* tau Proteins / metabolism*
IF 4.544
引用数 2
リソース情報
ショウジョウバエ 8203R-1