@article{96b754b61c724a9294bb2242f293f691,
title = "Cyclin-Dependent Kinase 5–Dependent BAG3 Degradation Modulates Synaptic Protein Turnover",
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.",
keywords = "Alzheimer's disease, BAG3, CDK5, HSP70, Signaling, Synaptic function",
author = "Jiechao Zhou and Chow, {Hei Man} and Yan Liu and Di Wu and Meng Shi and Jieyin Li and Lei Wen and Yuehong Gao and Guimiao Chen and Kai Zhuang and Hui Lin and Guanyun Zhang and Wenting Xie and Huifang Li and Lige Leng and Mengdan Wang and Naizhen Zheng and Hao Sun and Yingjun Zhao and Yunwu Zhang and Maoqiang Xue and Huang, {Timothy Y.} and Guojun Bu and Huaxi Xu and Zengqiang Yuan and Karl Herrup and Jie Zhang",
note = "Funding Information: This work was supported by the National Science Foundation in China (Grant Nos. 31571055 , 81522016 , and 81271421 [to JZha]; Grant No. 81801337 [to LL]; and Grant Nos. 81774377 and 81373999 [to LW]); Fundamental Research Funds for the Central Universities of China –Xiamen University (Grant Nos. 20720150062 , 20720180049 , and 20720160075 [to JZha]); Fundamental Research Funds for Fujian Province University Leading Talents (Grant No. JAT170003 [to LL]); Hong Kong Research Grants Council (Grant Nos. HKUST12/CRF/13G , GRF660813 , GRF16101315 , and AoE/M-05/12 [to KH] and Grant Nos. GRF16103317 , GRF16100718 , and GRF16100219 [to H-MC]); Offices of Provost, VPRG, and Dean of Science, Hong Kong University of Science and Technology (Grant No. VPRGO12SC02 [to KH]); Chinese University of Hong Kong (CUHK) Improvement on Competitiveness in Hiring New Faculty Funding Scheme (Ref. No. 133); and CUHK Faculty Startup Fund and Alzheimer{\textquoteright}s Association Research Fellowship (Grant No. AARF-17-531566 [to H-MC]). JZho, H-MC, and JZha conceptualized the study. H-MC, YHG, and KZ designed and performed morphological analysis and biochemical assays. YHG, GC, JZho, JL, and MS performed behavior tests. DW performed pre-experiments. JZho, JL, MS, and KZ performed the AAV injection. JZho, JL, MS, HLi, LL, YHG, DW, and WX prepared and maintained the mice in Xiamen; H-MC did the same in Hong Kong. YL, YHG, NZ, and MW performed electrophysiology experiments and Golgi staining. LW and HS supervised the electrophysiology experiments. GC and HLin performed the primary neuronal culture. H-MC, KH, and JZha wrote the manuscript. YuZ, ZY, YiZ, TYH, HX, and GB discussed and edited the manuscript. JZha supervised the project. We acknowledge the generosity of many different laboratories in providing the majority of the DNA vectors used in this study. We also thank BrainVTA Co. for generating AAV particles. The authors report no biomedical financial interests or potential conflicts of interest. Funding Information: This work was supported by the National Science Foundation in China (Grant Nos. 31571055, 81522016, and 81271421 [to JZha]; Grant No. 81801337 [to LL]; and Grant Nos. 81774377 and 81373999 [to LW]); Fundamental Research Funds for the Central Universities of China?Xiamen University (Grant Nos. 20720150062, 20720180049, and 20720160075 [to JZha]); Fundamental Research Funds for Fujian Province University Leading Talents (Grant No. JAT170003 [to LL]); Hong Kong Research Grants Council (Grant Nos. HKUST12/CRF/13G, GRF660813, GRF16101315, and AoE/M-05/12 [to KH] and Grant Nos. GRF16103317, GRF16100718, and GRF16100219 [to H-MC]); Offices of Provost, VPRG, and Dean of Science, Hong Kong University of Science and Technology (Grant No. VPRGO12SC02 [to KH]); Chinese University of Hong Kong (CUHK) Improvement on Competitiveness in Hiring New Faculty Funding Scheme (Ref. No. 133); and CUHK Faculty Startup Fund and Alzheimer's Association Research Fellowship (Grant No. AARF-17-531566 [to H-MC]). JZho, H-MC, and JZha conceptualized the study. H-MC, YHG, and KZ designed and performed morphological analysis and biochemical assays. YHG, GC, JZho, JL, and MS performed behavior tests. DW performed pre-experiments. JZho, JL, MS, and KZ performed the AAV injection. JZho, JL, MS, HLi, LL, YHG, DW, and WX prepared and maintained the mice in Xiamen; H-MC did the same in Hong Kong. YL, YHG, NZ, and MW performed electrophysiology experiments and Golgi staining. LW and HS supervised the electrophysiology experiments. GC and HLin performed the primary neuronal culture. H-MC, KH, and JZha wrote the manuscript. YuZ, ZY, YiZ, TYH, HX, and GB discussed and edited the manuscript. JZha supervised the project. We acknowledge the generosity of many different laboratories in providing the majority of the DNA vectors used in this study. We also thank BrainVTA Co. for generating AAV particles. The authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: {\textcopyright} 2019 Society of Biological Psychiatry",
year = "2020",
month = apr,
day = "15",
doi = "10.1016/j.biopsych.2019.11.013",
language = "English (US)",
volume = "87",
pages = "756--769",
journal = "Biological Psychiatry",
issn = "0006-3223",
publisher = "Elsevier USA",
number = "8",
}