Zscan21, short for zinc finger and SCAN domain containing 21, is a transcription factor. It is involved in the transcriptional regulation of genes, with a significant association in the context of neurodegenerative diseases. Specifically, it plays a role in regulating the expression of SNCA, the gene encoding α -synuclein, which is strongly implicated in Parkinson disease (PD) [2,3,4,5,6]. It may also be involved in pathways related to Alzheimer's disease as its expression was associated with waist-to-hip ratio, an obesity metric, in relation to Alzheimer's disease-related gene expression [1].

In functional studies, silencing of Zscan21 in neuronal cells led to variable effects on SNCA expression. In primary neuronal cultures, lentivirus-mediated silencing increased SNCA promoter activity, mRNA, and protein levels in cortical cultures, while reducing it in neurosphere cultures [3]. In mouse models, efficient adeno-associated virus-mediated knockdown of Zscan21 in the postnatal and adult hippocampus did not result in significant alterations in SNCA levels, suggesting possible compensatory mechanisms in vivo [3]. Rare genetic variants in the Zscan21 gene were found in patients with familial forms of PD, and expression of these variants led to the stabilization of the Zscan21 protein, indicating its potential role in PD pathogenesis [2].

In conclusion, Zscan21 is a crucial transcription factor involved in the transcriptional regulation of SNCA, with implications for Parkinson disease. Mouse models, especially those utilizing knockdown techniques, have been instrumental in revealing its complex role in regulating SNCA expression in different neuronal contexts. Its association with Alzheimer's disease-related gene expression also highlights its potential importance in understanding the molecular links between obesity and neurodegenerative diseases.

References:

1. Charisis, Sokratis, Lin, Honghuang, Ray, Roshni, Sargurupremraj, Muralidharan, Satizabal, Claudia L. 2023. Obesity impacts the expression of Alzheimer's disease-related genes: The Framingham Heart Study. In Alzheimer's & dementia : the journal of the Alzheimer's Association, 19, 3496-3505. doi:10.1002/alz.12954. https://pubmed.ncbi.nlm.nih.gov/36811231/

2. Lassot, Iréna, Mora, Stéphan, Lesage, Suzanne, Brice, Alexis, Desagher, Solange. . The E3 Ubiquitin Ligases TRIM17 and TRIM41 Modulate α-Synuclein Expression by Regulating ZSCAN21. In Cell reports, 25, 2484-2496.e9. doi:10.1016/j.celrep.2018.11.002. https://pubmed.ncbi.nlm.nih.gov/30485814/

3. Dermentzaki, Georgia, Paschalidis, Nikolaos, Politis, Panagiotis K, Stefanis, Leonidas. 2016. Complex Effects of the ZSCAN21 Transcription Factor on Transcriptional Regulation of α-Synuclein in Primary Neuronal Cultures and in Vivo. In The Journal of biological chemistry, 291, 8756-72. doi:10.1074/jbc.M115.704973. https://pubmed.ncbi.nlm.nih.gov/26907683/

4. Wright, Josephine A, McHugh, Patrick C, Pan, Siyi, Cunningham, Adam, Brown, David R. 2013. Counter-regulation of alpha- and beta-synuclein expression at the transcriptional level. In Molecular and cellular neurosciences, 57, 33-41. doi:10.1016/j.mcn.2013.09.002. https://pubmed.ncbi.nlm.nih.gov/24080388/

5. Clough, Richard Lee, Dermentzaki, Georgia, Stefanis, Leonidas. 2009. Functional dissection of the alpha-synuclein promoter: transcriptional regulation by ZSCAN21 and ZNF219. In Journal of neurochemistry, 110, 1479-90. doi:10.1111/j.1471-4159.2009.06250.x. https://pubmed.ncbi.nlm.nih.gov/19549071/

6. Brenner, Steffen, Wersinger, Christophe, Gasser, Thomas. 2015. Transcriptional regulation of the α-synuclein gene in human brain tissue. In Neuroscience letters, 599, 140-5. doi:10.1016/j.neulet.2015.05.029. https://pubmed.ncbi.nlm.nih.gov/26002080/