In this work, published in Cell Reports, Lassot et al. (« Molecular Mechanisms of Apoptosis Regulation»; Solange Desagher) describe a pathway regulating α-synuclein expression with in vivo and pathological relevance. Parkinson’s disease (PD) is one of the most common neurodegenerative disorders. Although most cases of PD are sporadic, over 10% are associated with mutations in genes. SNCA, which encodes α-synuclein, is arguably the most important gene linked to PD. Notably, many studies suggest that even a moderate increase of wild type (WT) α-synuclein is enough to cause both inherited and sporadic forms of PD. Indeed, duplications or triplications of the WT SNCA locus give rise to dominantly inherited PD; the severity of the disease being directly correlated with α-synuclein mRNA and protein levels and genetic variability in the promoter region of SNCA associated with increased risk for PD has also been correlated with upregulation of α-synuclein expression. However, mechanisms regulating the transcription of SNCA are largely unknown. In this study, authors show that the transcription factor ZSCAN21 stimulates SNCA transcription in neuronal cells and that TRIM41 is an E3 ubiquitin-ligase for ZSCAN21. In contrast, TRIM17 decreased the TRIM41-mediated degradation of ZSCAN21. The mRNA levels of TRIM17, ZSCAN21 and SNCA were simultaneously increased in midbrains of mice model of PD. Furthermore, their genetic data from patients suggest that a deregulation of this pathway might be involved in the pathogenesis of PD. As such, this study may pave the road for the development of neuroprotective therapeutic strategies aiming at restoring a level of α-synuclein compatible with the function and survival of dopaminergic neurons.
“The E3 ubiquitin-ligases TRIM17 and TRIM41 modulate α-synuclein expression by regulating ZSCAN21.”
Iréna Lassot, Stéphan Mora, Suzanne Lesage, Barbara A Zieba, Emmanuelle Coque , Christel Condroyer, Jozef Piotr Bossowski, Barbara Mojsa, Cecilia Marelli, Caroline Soulet, Christelle Tesson, Iria Carballo-Carbajal, Ariadna Laguna, Graziella Mangone, Miquel Vila, Alexis Brice, Solange Desagher.
Open AccessPublished: November 27, 2018DOI:https://doi.org/10.1016/j.celrep.2018.11.002