TY - JOUR
T1 - The E3 Ubiquitin Ligases TRIM17 and TRIM41 Modulate α-Synuclein Expression by Regulating ZSCAN21
AU - Lassot, Iréna
AU - Mora, Stéphan
AU - Lesage, Suzanne
AU - Zieba, Barbara A.
AU - Coque, Emmanuelle
AU - Condroyer, Christel
AU - Bossowski, Jozef Piotr
AU - Mojsa, Barbara
AU - Marelli, Cecilia
AU - Soulet, Caroline
AU - Tesson, Christelle
AU - Carballo-Carbajal, Iria
AU - Laguna, Ariadna
AU - Mangone, Graziella
AU - Vila, Miquel
AU - Brice, Alexis
AU - Desagher, Solange
PY - 2018/11/27
Y1 - 2018/11/27
N2 - © 2018 The Author(s) 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. Although α-synuclein expression plays a crucial role in Parkinson disease (PD), its transcriptional regulation is largely unknown. Lassot et al. describe a pathway regulating α-synuclein expression. Identification and characterization of genetic variations in patients suggest that deregulation of this pathway may be involved in the pathogenesis of PD.
AB - © 2018 The Author(s) 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. Although α-synuclein expression plays a crucial role in Parkinson disease (PD), its transcriptional regulation is largely unknown. Lassot et al. describe a pathway regulating α-synuclein expression. Identification and characterization of genetic variations in patients suggest that deregulation of this pathway may be involved in the pathogenesis of PD.
KW - E3 ubiquitin-ligases
KW - Parkinson disease
KW - transcriptional regulation
KW - TRIM17
KW - TRIM41
KW - ubiquitin-proteasome system
KW - ZSCAN21
KW - α-synuclein/SNCA
U2 - 10.1016/j.celrep.2018.11.002
DO - 10.1016/j.celrep.2018.11.002
M3 - Article
VL - 25
SP - 2484-2496.e9
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
ER -