Usp14 deficiency removes α-synuclein by regulating S100A8/A9 in Parkinson’s disease

作者：Liuyan Ding, Lin Lü, Shaohui Zheng, Zhiling Zhang, Xingting Huang, Runfang Ma, Mengran Zhang, Zongtang Xu, Minshan Chen, Zhimei Guo, Si Zhu, Junwei Gong, Hengxu Mao, Wenlong Zhang, Pingyi Xu · 发表于：Cellular and Molecular Life Sciences · 年份：2024 · DOI：10.1007/s00018-024-05246-8 · 被引用次数：17 · 研究领域：Parkinson's Disease Mechanisms and Treatments、Alzheimer's disease research and treatments、Genetic Neurodegenerative Diseases

Abstract Ubiquitin-proteasome system dysfunction triggers α-synuclein aggregation, a hallmark of neurodegenerative diseases, such as Parkinson’s disease (PD). However, the crosstalk between deubiquitinating enzyme (DUBs) and α-synuclein pathology remains unclear. In this study, we observed a decrease in the level of ubiquitin-specific protease 14 (USP14), a DUB, in the cerebrospinal fluid (CSF) of PD patients, particularly females. Moreover, CSF USP14 exhibited a dual correlation with α-synuclein in male and female PD patients. To investigate the impact of USP14 deficiency, we crossed USP14 heterozygous mouse (USP14 +/− ) with transgenic A53T PD mouse (A53T-Tg) or injected adeno-associated virus (AAV) carrying human α-synuclein (AAV- h α-Syn) in USP14 +/− mice. We found that Usp14 deficiency improved the behavioral abnormities and pathological α-synuclein deposition in female A53T-Tg or AAV- h α-Syn mice. Additionally, Usp14 inactivation attenuates the pro-inflammatory response in female AAV- h α-Syn mice, whereas Usp14 inactivation demonstrated opposite effects in male AAV- h α-Syn mice. Mechanistically, the heterodimeric protein S100A8/A9 may be the downstream target of Usp14 deficiency in female mouse models of α-synucleinopathies. Furthermore, upregulated S100A8/A9 was responsible for α-synuclein degradation by autophagy and the suppression of the pro-inflammatory response in microglia after Usp14 knockdown. Consequently, our study suggests that USP14 could serve as a nov...