Ctsd, also known as cathepsin D, is a lysosomal aspartic protease. It has a vital role in maintaining cellular homeostasis, especially in neurons where it regulates the proteolytic activity of lysosomes [2]. It is involved in autophagy and lysosomal pathways and has been associated with multiple biological processes such as apoptosis and cell proliferation [3]. Genetic models, like knockout mouse models, have been crucial in studying its function.

In ctsd-deficient mouse models, there is an accumulation of insoluble SNCA conformers in the brain, indicating Ctsd's critical role in SNCA/α-synuclein clearance, and its deficiency may be linked to the transcellular transmission of SNCA aggregates. Boosting lysosomal Ctsd activity not only enhanced SNCA clearance but also restored endo-lysosome and autophagy function, suggesting potential therapeutic value for Parkinson disease and other synucleinopathies [1]. In stroke models, a time-dependent decrease in Ctsd protein levels and activity was observed in the mouse brain, along with lysosomal dysfunction. ShRNA-mediated knockdown of Ctsd in neurons aggravated lysosomal dysfunction and cell death, while restoration of Ctsd protein levels via lentiviral transduction increased its activity and rendered resistance to oxygen-glucose deprivation-mediated defects, highlighting the importance of Ctsd-dependent lysosomal function in maintaining neuronal survival in cerebral ischemia [2].

In conclusion, Ctsd is essential for maintaining cellular homeostasis, especially in neurons, through its role in lysosomal proteolytic activity. Studies using gene knockout mouse models have revealed its significance in neurodegenerative diseases like Parkinson disease and stroke, providing insights into potential therapeutic strategies targeting Ctsd-related pathways for these conditions.