SNCA, also known as synuclein alpha, encodes α-synuclein, a protein that is the major component of Lewy bodies and Lewy neurites, the pathognomonic hallmarks of Parkinson's disease (PD) [3]. Although its exact physiological function remains unclear, it has been implicated in processes such as synaptic vesicle trafficking and neurotransmitter release. Genome-wide association studies have shown that SNCA is associated with the etiology of synucleinopathies, and its expression levels are considered critical for the development of these diseases [2,4].

In PD, the abnormal intracellular accumulation of SNCA/α-synuclein is a characteristic feature. Studies suggest that lysosomal deficiencies and autophagy are involved in SNCA pathology. Cathepsin D (CTSD), a major lysosomal protease, is proposed to be involved in SNCA degradation. In ctsd-deficient mouse models, dosing with recombinant human pro-CTSD (rHsCTSD) decreased pathological SNCA conformers in the brain and primary neurons, enhanced SNCA clearance in human and murine neurons and tissue, and restored endo-lysosome and autophagy function [1].

In conclusion, SNCA is a crucial gene in the context of synucleinopathies, especially PD. Research using mouse models, such as the ctsd-deficient model, has provided insights into the role of SNCA in disease pathology, particularly in relation to lysosomal degradation pathways. Understanding SNCA's function and its regulation may offer potential therapeutic strategies for treating PD and other synucleinopathies.

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/