The E3 Ubiquitin Ligases TRIM17 and TRIM41 Modulate α-Synuclein Expression by Regulating ZSCAN21

Cell Rep. 2018 Nov 27;25(9):2484-2496.e9. doi: 10.1016/j.celrep.2018.11.002.

Abstract

Although accumulating data indicate that increased α-synuclein expression is crucial for Parkinson disease (PD), mechanisms regulating the transcription of its gene, SNCA, are largely unknown. Here, we describe a pathway regulating α-synuclein expression. Our data show that ZSCAN21 stimulates SNCA transcription in neuronal cells and that TRIM41 is an E3 ubiquitin ligase for ZSCAN21. In contrast, TRIM17 decreases the TRIM41-mediated degradation of ZSCAN21. Silencing of ZSCAN21 and TRIM17 consistently reduces SNCA expression, whereas TRIM41 knockdown increases it. The mRNA levels of TRIM17, ZSCAN21, and SNCA are simultaneously increased in the midbrains of mice following MPTP treatment. In addition, rare genetic variants in ZSCAN21, TRIM17, and TRIM41 genes occur in patients with familial forms of PD. Expression of variants in ZSCAN21 and TRIM41 genes results in the stabilization of the ZSCAN21 protein. Our data thus suggest that deregulation of the TRIM17/TRIM41/ZSCAN21 pathway may be involved in the pathogenesis of PD.

Keywords: E3 ubiquitin-ligases; Parkinson disease; TRIM17; TRIM41; ZSCAN21; transcriptional regulation; ubiquitin-proteasome system; α-synuclein/SNCA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Carrier Proteins / metabolism*
  • Cell Line
  • Female
  • Gene Expression Regulation
  • Humans
  • Kruppel-Like Transcription Factors / chemistry
  • Kruppel-Like Transcription Factors / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Mutation / genetics
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / metabolism*
  • Pedigree
  • Protein Binding
  • Proteolysis
  • Trans-Activators / metabolism*
  • Transcription, Genetic
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*

Substances

  • Carrier Proteins
  • Kruppel-Like Transcription Factors
  • Nuclear Proteins
  • Trans-Activators
  • ZSCAN21 protein, human
  • Zscan21 protein, mouse
  • alpha-Synuclein
  • TRIM17 protein, human
  • TRIM41 protein, human
  • Trim17 protein, mouse
  • Trim41 protein, mouse
  • Ubiquitin-Protein Ligases