SNCA, also known as synuclein alpha, encodes the α -synuclein protein. α -synuclein is the major component of Lewy bodies and Lewy neurites, which are pathognomonic hallmarks of Parkinson's disease (PD) and other synucleinopathies [3]. The gene has been implicated in the etiology of these neurodegenerative diseases, and its expression levels seem to be critical for disease development [2,4].

In PD models, abnormal intracellular accumulation of SNCA/α -synuclein occurs. Lysosomal protease cathepsin D (CTSD) has been proposed to be involved in SNCA degradation. Deficiency of CTSD is linked to the presence of insoluble SNCA conformers and their transcellular transmission. Treatment with recombinant human pro-form of CTSD (rHsCTSD) enhanced SNCA degradation in PD patient-derived dopaminergic neurons and in a ctsd-deficient mouse model, and also restored endo-lysosome and autophagy function [1].

In conclusion, SNCA is central to the pathogenesis of synucleinopathies, especially PD. Mouse models, such as the ctsd-deficient mouse model, have been valuable in revealing the role of factors like CTSD in regulating SNCA degradation, providing insights into potential therapeutic strategies for PD and other related neurodegenerative diseases.

References:

1. Prieto Huarcaya, Susy, Drobny, Alice, Marques, André R A, Saftig, Paul, Zunke, Friederike. 2022. Recombinant pro-CTSD (cathepsin D) enhances SNCA/α-Synuclein degradation in α-Synucleinopathy models. In Autophagy, 18, 1127-1151. doi:10.1080/15548627.2022.2045534. https://pubmed.ncbi.nlm.nih.gov/35287553/

2. Chiba-Falek, Ornit. 2017. Structural variants in SNCA gene and the implication to synucleinopathies. In Current opinion in genetics & development, 44, 110-116. doi:10.1016/j.gde.2017.01.014. https://pubmed.ncbi.nlm.nih.gov/28319736/

3. Xu, Wei, Tan, Lan, Yu, Jin-Tai. 2014. Link between the SNCA gene and parkinsonism. In Neurobiology of aging, 36, 1505-18. doi:10.1016/j.neurobiolaging.2014.10.042. https://pubmed.ncbi.nlm.nih.gov/25554495/

4. Tagliafierro, L, Chiba-Falek, O. 2016. Up-regulation of SNCA gene expression: implications to synucleinopathies. In Neurogenetics, 17, 145-57. doi:10.1007/s10048-016-0478-0. https://pubmed.ncbi.nlm.nih.gov/26948950/