CTSD

CTSD, short for cathepsin D, is a lysosomal aspartic protease of the peptidase A1 family. In humans, CTSD refers to both the CTSD gene and the mature enzyme it encodes. The enzyme is synthesized as a preproenzyme with an N-terminal signal peptide and a propeptide and is trafficked to the endolysosomal system, where proteolytic processing removes the propeptide to generate the active enzyme composed of heavy and light chains linked by a disulfide bond. Cathepsin D operates optimally in acidic conditions, typically within the lysosome (pH around 3.5–4.5).

Functionally, CTSD contributes to intracellular protein turnover by degrading autophagic cargo and endocytosed substrates. It also participates in antigen processing within the endolysosome and can influence extracellular remodeling when secreted or released into the cytosol. In addition to its normal housekeeping roles, CTSD participates in apoptotic signaling, including pathways that involve mitochondrial disruption and cleavage of substrates such as Bid under certain conditions.

Clinical significance and regulation: Altered CTSD expression and activity have been associated with aging and neurodegenerative diseases, including Alzheimer’s disease, as well as with cancer progression, invasion, metastasis, and chemoresistance in several tumor types. Because of its involvement in lysosomal function and cell death pathways, CTSD is studied as a potential biomarker and therapeutic target, with inhibitors of aspartic proteases (such as pepstatin A) used to study its activity. Mutations in CTSD can cause a rare form of neuronal ceroid lipofuscinosis (CLN10), a neurodegenerative lysosomal storage disorder.