Regulation of USP25 by SP1 Associates with Amyloidogenesis

J Alzheimers Dis. 2023;92(4):1459-1472. doi: 10.3233/JAD-221184.

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; Ubiquitin Specific Peptidase 25; gene regulation; specificity protein 1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Promoter Regions, Genetic
  • Signal Transduction*
  • Sp1 Transcription Factor* / genetics
  • Sp1 Transcription Factor* / metabolism
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / metabolism

Substances

  • Sp1 Transcription Factor
  • USP25 protein, human
  • Ubiquitin Thiolesterase
  • SP1 protein, human