Disease relevance of CTSD

• Cathepsin D (CTSD) is a lysosomal protease involved in the pathogenesis of several diseases such as breast cancer and possibly Alzheimer's disease (AD) [1].
• Inhibition of CTSD in mouse DSS colitis was followed by an amelioration of the disease [2].
• We have shown previously an induction of CTSD expression in intestinal macrophages (IMAC) in inflamed mucosa of patients with inflammatory bowel disease (IBD) [2].
• After cataract surgery, the CPSD index worsened in many subjects with dense scotomas [3].

Psychiatry related information on CTSD

• The cathepsin D gene (CTSD) exon 2 (C224T) polymorphism has been associated with an increased risk for sporadic Alzheimer's disease (AD), but with controversial findings [4].
• In contrast, CTSD T/APOEepsilon4-positive volunteers scored lower on tests of fluid intelligence (P = 0.015), processing speed (ACT, P = 0.001; RL, P = 0.013) and immediate recall (P = 0.029) [5].

High impact information on CTSD

• The mean residence time of cathepsin D precursor in coated membranes was estimated to be 2 min [6].
• The extraction of this cathepsin D precursor was independent of mannose 6-phosphate and was complete after a brief exposure to saponin [6].
• Two missense mutations in the CTSD gene, F229I and W383C, were identified and were found to cause markedly reduced proteolytic activity and a diminished amount of cathepsin D in patient fibroblasts [7].
• In HL-60R cells, none of the agents alone or in combination significantly enhances the expression of the ctsd, IL-8, or ctsl mRNAs [8].
• In HL-60 cells, cathepsin D (ctsd) mRNA levels are increased by these agents and by cholera toxin after pretreatment with each agent [8].

Chemical compound and disease context of CTSD

• Cathepsin inhibition was investigated in the dextran-sulphate-sodium (DSS) colitis model in mice with application of pepstatin A (CTSD inhibitor), CA-074 (CTSB inhibitor) and Z-Phe-Tyr-aldehyde (CTSL inhibitor) [2].

Biological context of CTSD

• The T allele of the CTSD genotype was associated with a 50% decrease in Abeta(42) levels in the cerebrospinal fluid [9].
• Thus, if sequence variations within the CTSD gene influence the risk for various diseases, the pathogenic mechanism is likely to be linked to the amino acid substitution in the profragment of CTSD [1].
• The regional differences in CTSD allele frequencies could be related to the different patterns of association between this polymorphism and AD in various European studies [4].
• Transmission analysis in a 99 dog pedigree of American Bulldogs indicated a probability of less than 10(-7) that alleles from any mutation unlinked to CTSD would be concordant with the pedigree and phenotypes of the dogs [10].
• Furthermore, low CTSD was significantly associated with serous histology and advanced tumor stage [11].

Anatomical context of CTSD

• Interestingly, CTSD is transported by IGF2R from the trans Golgi network to the lysosome [12].
• Thus, we demonstrate a significant impact of the CTSD genotype on Abeta(42) levels in the cerebrospinal fluid of AD patients and underpin the importance of the validation of susceptibility genes by examining their potential pathophysiological relevance [9].
• Of particular note, expression of cathepsin D (CTSD), a lysosomal proteinase, was reduced by approximately 50% in monocyte-derived macrophages of low HDL-C subjects, most significantly those with cholesterol efflux defects but without mutations in ABCA1 (p < 0.01) [13].
• Consistent with its role in the proteolytic processing of prosaposin, inactivation of CTSD function resulted in the accumulation of glycosphingo-lipid and free cholesterol in late endosomes/lysosomes, a phenotype similar to NPC1 deficiency [13].
• Inhibition of CTSD also caused retention of ABCA1 in lysosomal compartments, reducing its trafficking to the plasma membrane [13].

Associations of CTSD with chemical compounds

• Ceramide specifically binds to and induces CTSD proteolytic activity [14].
• These studies demonstrate a novel and potentially important role for CTSD in intracellular cholesterol trafficking and ABCA1-mediated efflux [13].
• In secretions of [(33)P]phosphate-labelled macrophages no or weakly phosphorylated ASA and CTSD precursor polypeptides were found, whereas both intracellular and secreted ASA from ASA-overexpressing baby hamster kidney cells displayed (33)P-labelled M6P residues [15].
• All of the monocytic inducers stimulate ctsd mRNA, and both calcitriol and sodium butyrate significantly potentiate the subsequent response to retinoic acid [16].
• Pretreatment with retinoic acid enhances the response of the ctsd gene to prostaglandin E2 [16].

Enzymatic interactions of CTSD

• CTSD may play a role in Alzheimer's disease (AD) through cleaving the amyloid precursor protein into beta-amyloid peptide and degrading tau protein into fragments [17].

Other interactions of CTSD

• No statistically significant differences were found in CTSD allele or genotype frequencies between AD patients and controls, and there were no interactions with sex or APOE genotype [4].
• Two mutations have been described in animal genes (cln8/mnd, CTSD) [18].
• Aspartyl protease Cathepsin D (CTSD) has been suggested to play a role in the pathogenesis of sporadic Alzheimer's disease (AD) due to interference with protein degradation mechanisms [19].
• The exonic regions of the CTSD gene were screened for further polymorphic variations using polymerase chain reaction and single-strand conformation polymorphism analysis [1].
• Mutations in two additional genes cause disease in animal models that share features with NCL-CTSD in sheep and mice and PPT2 in mice [20].

Analytical, diagnostic and therapeutic context of CTSD

• We observed a significant association (P = 0.01) between a functional C > T (Ala > Val) transition within exon 2 of the CTSD gene that increases the secretion of pro-CTSD from the cell, and the AH4-1 score at initial testing on entry to the longitudinal study [12].
• Two recent case-control studies have suggested a strong association of a missense polymorphism in exon 2 of the cathepsin D gene (CTSD) and Alzheimer disease (AD) [21].
• The authors performed a meta-analysis of 14 studies (16 comparisons) with CTSD genotyping (3,174 Alzheimer's disease cases and 3,298 controls) [22].
• CTSD and APOE genotyping were performed by PCR on DNA extracted from blood, or from frontal cortex or cerebellum in the postmortem cases [23].
• Blue-on-yellow perimetry showed a significant reduction in CPSD from 3.81 +/- 1.60 to 2.71 +/- 1.92 (p < 0.05) [24].

References