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Elevated phosphorylated ubiquitin level elicits neurodegeneration by aggregating the decline of ubiquitindependent proteasomal degradation

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中国药理学与毒理学杂志 2023年第7期37卷 516-517页

作者： CHEN Cong GAO Tongyao WANG Tong LU Yunbi ZHANG Weiping Department of Pharmacology School of Medicine Zhejiang University

OBJECTIVE To determine the roles of phosphorylated ubiquitin(pUb) on ubiquitin-dependent proteasomal(UPS) degradation activity, and the roles of pUb on neurodegeneration. METHODS We use PTEN induced kinase 1(PINK1) to phosphorylate ubiquitin. The Ub/S65A cannot be phosphorylated by PINK1, and was used to antagonize the roles of pUb. The Ub/S65E was used to mimic the roles of pUb. The roles of pUb on UPS degradation activity were determined by immunofluorescence, Western blot and TIRF microscope at cellular and protein level. The roles of pUb on neurodegeneration were determined by behavior tests, immunofluorescence,Golgi staining, TEM, Western blot and proteomics sacle in mouse. RESULTS The level of soluble PINK1(sPINK1)and pUb increased in the neurons of aged mouse brain,and in the cells upon the administration of MG132, a proteasome inhibitor. The elevation of sPINK1 and pUb was accompanied by protein aggregation upon aging or the proteasomal inhibition. The pink1 knockout alleviated proteasomal inhibition induced protein aggregation and association of ubiquitinated proteins with proteasome.The over-expression of sPINK1 increased pUb level in hippocampal neuron, which chronically induced protein aggregation, mitochondrial damage and damage the structure of neuronal spines. Such neuronal injury lead to cognitive impairment of mice. The roles of sPINK1 was reversed by co-expression with Ub/S65A, and was mimic by over-expression with Ub/S65E. CONCLUSION The phosphorylation of ubiquitin aggravates UPS degradation, and accelerates neuronal degeneration upon the decline of proteasomal degradation in aging and agerelated neuronal diseases.

关键词： aging neurodegeneration phosphorylated ubiquitin proteasome protein aggregation PTEN induced kinase 1

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