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

Ubiquitin-proteasome system dysfunction triggers alpha-synuclein aggregation, a hallmark of neurodegenerative diseases, such as Parkinson's disease (PD). However, the crosstalk between deubiquitinating enzyme (DUBs) and alpha-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 alpha-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 alpha-synuclein (AAV-h alpha-Syn) in USP14+/- mice. We found that Usp14 deficiency improved the behavioral abnormities and pathological alpha-synuclein deposition in female A53T-Tg or AAV-h alpha-Syn mice. Additionally, Usp14 inactivation attenuates the pro-inflammatory response in female AAV-h alpha-Syn mice, whereas Usp14 inactivation demonstrated opposite effects in male AAV-h alpha-Syn mice. Mechanistically, the heterodimeric protein S100A8/A9 may be the downstream target of Usp14 deficiency in female mouse models of alpha-synucleinopathies. Furthermore, upregulated S100A8/A9 was responsible for alpha-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 novel therapeutic target in PD.