Regulation of USP25 by SP1 Associates with Amyloidogenesis

Article type: Research Article

Authors: Li, Ran^{a; b; 1} | Song, Beibei^{c; 1} | Xu, Lu^b | Zheng, Jiali^b | Pan, Wenhao^b | Cai, Fang^c | Wang, Juelu^c | Wu, Yili^{b; d; *} | Song, Weihong^{a; b; c; d; *}

Affiliations: [a] The Second Affiliated Hospital and Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China | [b] Institute of Aging, Key Laboratory of Alzheimer’s Disease of Zhejiang Province,Zhejiang Provincial Clinical Research Center for Mental Disorders, School of Mental Health and Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China | [c] Townsend Family Laboratories, Department of Psychiatry, Graduate Program in Neuroscience, The University of British Columbia, Vancouver, BC, Canada | [d] Oujiang Laboratory Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Wenzhou, Zhejiang, China

Correspondence: [*] Correspondence to: Dr. Weihong Song, Chashan District, Wenzhou, Zhejiang 325000, China. Tel.: +86 057786699670; E-mail: [email protected] and Dr. Yili Wu, Chashan District, Wenzhou, Zhejiang, China. Tel.: +86 057786699661; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Background:Trisomy 21, an extra copy of human chromosome 21 (HSA21), causes most Down’s syndrome (DS) cases. Individuals with DS inevitably develop Alzheimer’s disease (AD) neuropathological phenotypes after middle age including amyloid plaques and tau neurofibrillary tangles. Ubiquitin Specific Peptidase 25 (USP25), encoding by USP25 gene located on HSA21, is a deubiquitinating enzyme, which plays an important role in both DS and AD pathogenesis. However, the regulation of USP25 remains unclear. Objective:We aimed to determine the regulation of USP25 by specificity protein 1 (SP1) in neuronal cells and its potential role in amyloidogenesis. Methods:The transcription start site and promoter activity was identified by SMART-RACE and Dual-luciferase assay. Functional SP1-responsive elements were examined by EMSA. USP25 expression was examined by RT-PCR and immunoblotting. Student’s t-test or one-way ANOVA were applied or statistical analysis. Results:The transcription start site of human USP25 gene was identified. Three functional SP1 responsive elements in human USP25 gene were revealed. SP1 promotes USP25 transcription and subsequent USP25 protein expression, while SP1 inhibition significantly reduces USP25 expression in both non-neuronal and neuronal cells. Moreover, SP1 inhibition dramatically reduces amyloidogenesis. Conclusion:We demonstrates that transcription factor SP1 regulates USP25 gene expression, which associates with amyloidogenesis. It suggests that SP1 signaling may play an important role in USP25 regulation and contribute to USP25-mediated DS and AD pathogenesis.

Keywords: Amyloidogenesis, gene regulation, specificity protein 1, Ubiquitin Specific Peptidase 25

DOI: 10.3233/JAD-221184

Journal: Journal of Alzheimer's Disease, vol. 92, no. 4, pp. 1459-1472, 2023