ZSCAN21 mediates the pathogenic transcriptional induction of α-synuclein in cellular and animal models of Parkinson’s disease

The expression level of α-synuclein is thought to play a crucial role in the pathogenesis of Parkinson's disease. However, little is known about the molecular mechanisms regulating the transcription of its gene, SNCA, particularly in the context of the disease. The transcription factor ZSCAN21 has been shown to act on SNCA, but whether ZSCAN21 is actually involved in the induction of SNCA transcription in Parkinson's disease is unknown. To address this question, we used the MPTP mouse model and LUHMES-derived dopaminergic neuronal spheroids, subjected to Parkinson's disease-related neurotoxins and mutations. We show that MPP⁺-treated spheroids recapitulate the main features of α-synuclein pathology and that MPP⁺-triggered transcriptional induction of SNCA is associated with ZSCAN21 stabilisation. Importantly, knock-down of ZSCAN21 prevents both the MPP⁺-triggered increase in α-synuclein mRNA and pre-mRNA levels in LUHMES-derived spheroids and the death of dopaminergic neurons in the substantia nigra of MPTP-treated mice. These effects are recapitulated by knockdown of TRIM17, a ZSCAN21 stabiliser which prevents its ubiquitination and degradation mediated by TRIM41. Moreover, reducing the interaction between ZSCAN21 and TRIM41, either by inserting Parkinson's disease-associated mutations into the TRIM41 gene or by preventing SUMOylation of ZSCAN21, results in both stabilisation of ZSCAN21 and induction of SNCA. Taken together, our data strongly suggest that ZSCAN21 is a crucial transcription factor for pathogenic α-synuclein expression and neurodegeneration in Parkinson's disease, pointing to its regulators, TRIM17 and TRIM41, as original therapeutic targets for a neuroprotective treatment of Parkinson's disease.