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) [5]. It has been implicated in the etiology of synucleinopathies, and its expression levels seem to be critical for the development of these diseases [4,6].

In PD, abnormal intracellular accumulation of SNCA/α-synuclein occurs. Deficiency of CTSD, a lysosomal protease proposed to be involved in SNCA degradation, has been linked to insoluble SNCA conformers and their transcellular transmission. Recombinant human pro-CTSD enhances SNCA degradation in α-Synucleinopathy models, restoring endo-lysosome and autophagy function [1]. Also, studies show higher levels of SNCA mRNA in sporadic PD post-mortem midbrain tissues and substantia nigra dopaminergic neurons, suggesting that regulating SNCA expression could be an effective treatment approach for PD [2]. Neuronal SNCA transcription during Lewy body formation shows that preserved cellular SNCA expression in non-Lewy body type α-syn cytopathologies might provide a pool for protein aggregation, while successful segregation of disease-associated α-syn is related to SNCA production exhaustion in Lewy bodies, informing LBD therapy development targeting SNCA transcription [3].

In conclusion, SNCA is central to the pathogenesis of synucleinopathies, especially PD. Research on SNCA, including through gene-based models, has enhanced our understanding of its role in these diseases, potentially paving the way for new therapeutic strategies targeting SNCA expression and α-synuclein degradation.