Cyclin-Dependent Kinase 5–Dependent BAG3 Degradation Modulates Synaptic Protein Turnover

Jiechao Zhou, Hei Man Chow, Yan Liu, Di Wu, Meng Shi, Jieyin Li, Lei Wen, Yuehong Gao, Guimiao Chen, Kai Zhuang, Hui Lin, Guanyun Zhang, Wenting Xie, Huifang Li, Lige Leng, Mengdan Wang, Naizhen Zheng, Hao Sun, Yingjun Zhao, Yunwu ZhangMaoqiang Xue, Timothy Y. Huang, Guojun Bu, Huaxi Xu, Zengqiang Yuan, Karl Herrup, Jie Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Synaptic protein dyshomeostasis and functional loss is an early invariant feature of Alzheimer's disease (AD), yet the unifying etiological pathway remains largely unknown. Knowing that cyclin-dependent kinase 5 (CDK5) plays critical roles in synaptic formation and degeneration, its phosphorylation targets were reexamined in search of candidates with direct global impacts on synaptic protein dynamics, and the associated regulatory network was also analyzed. Methods: Quantitative phosphoproteomics and bioinformatics analyses were performed to identify top-ranked candidates. A series of biochemical assays was used to investigate the associated regulatory signaling networks. Histological, electrochemical, and behavioral assays were performed in conditional knockout, small hairpin RNA–mediated knockdown, and AD-related mice models to evaluate the relevance of CDK5 to synaptic homeostasis and functions. Results: Among candidates with known implications in synaptic modulations, BAG3 ranked the highest. CDK5-mediated phosphorylation on S297/S291 (mouse/human) destabilized BAG3. Loss of BAG3 unleashed the selective protein degradative function of the HSP70 machinery. In neurons, this resulted in enhanced degradation of a number of glutamatergic synaptic proteins. Conditional neuronal knockout of Bag3 in vivo led to impairment of learning and memory functions. In human AD and related mouse models, aberrant CDK5-mediated loss of BAG3 yielded similar effects on synaptic homeostasis. Detrimental effects of BAG3 loss on learning and memory functions were confirmed in these mice, and such effects were reversed by ectopic BAG3 reexpression. Conclusions: Our results highlight that the neuronal CDK5-BAG3-HSP70 signaling axis plays a critical role in modulating synaptic homeostasis. Dysregulation of the signaling pathway directly contributes to synaptic dysfunction and AD pathogenesis.

Original languageEnglish (US)
Pages (from-to)756-769
Number of pages14
JournalBiological psychiatry
Volume87
Issue number8
DOIs
StatePublished - Apr 15 2020

Keywords

  • Alzheimer's disease
  • BAG3
  • CDK5
  • HSP70
  • Signaling
  • Synaptic function

ASJC Scopus subject areas

  • Biological Psychiatry

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