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

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

Author information

1
Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France. Electronic address: irena.lassot@igmm.cnrs.fr.
2
Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France.
3
Sorbonne Universités, UPMC Université de Paris 06, UMR S 1127, Institut du Cerveau et de la Moelle épinière (ICM), Paris, France; INSERM U 1127, CNRS UMR 7225, AP-HP, Pitié-Salpêtrière Hospital, Paris, France.
4
Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute (VHIR)-Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), 08035 Barcelona, Spain.
5
Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute (VHIR)-Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), 08035 Barcelona, Spain; Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, 08193 Barcelona, Spain; Catalan Institution for Research and Advanced Studies (ICREA), 08010 Barcelona, Spain.

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

PMID:
30485814
DOI:
10.1016/j.celrep.2018.11.002
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