Disease relevance of Ctsa

• Galactosialidosis (GS) is a human neurodegenerative disease caused by a deficiency of lysosomal protective protein/cathepsin A (PPCA) [1].
• Lactacystin inhibits cathepsin A activity in melanoma cell lines [2].

High impact information on Ctsa

• The lysosomal storage disorder galactosialidosis results from a primary deficiency of the protective protein/cathepsin A (PPCA), which in turn affects the activities of beta-galactosidase and neuraminidase [3].
• Mice homozygous for a null mutation at the PPCA locus present with signs of the disease shortly after birth and develop a phenotype closely resembling human patients with galactosialidosis [3].
• To rescue the disease phenotype, GS mice were transplanted with bone marrow from transgenic mice overexpressing human PPCA specifically in monocytes/macrophages under the control of the colony stimulating factor-1 receptor promoter [1].
• PPCA-expressing perivascular and leptomeningeal macrophages were detected throughout the brain of recipient mice, although some neuronal cells, such as Purkinje cells, continued to show storage and died [1].
• Here, we established stable donor hematopoiesis in PPCA(-/-) mice that received hematopoietic progenitors transduced with a murine stem cell virus (MSCV)-based, bicistronic retroviral vector overexpressing PPCA and the green fluorescent protein (GFP) marker [4].

Chemical compound and disease context of Ctsa

• Other proteasome-specific inhibitors, e.g. epoxomicin and N-benzyloxycarbonyl-Ile-Glu(O-tert-Bu)-Ala-leucinal (PSI) at a concentration of 1 microM did not affect cathepsin A activity in melanoma cell line lysates [2].

Biological context of Ctsa

• Loci mapping between the T2Wa and T28H breakpoints lie in a region that is subject to parental imprinting, and so expression of Ppgb was tested in mice with maternal duplication/paternal deficiency and its reciprocal for the distal region of Chr 2 [5].
• Protective protein for beta-galactosidase, Ppgb, maps to the distal imprinting region of mouse chromosome 2 but is not imprinted [5].
• To study the site and level of expression of PPCA mRNA in murine and human tissues, we analyzed the promoter regions of the corresponding genes [6].
• Molecular cloning and gene expression studies have disclosed that protective protein is cathepsin A [7].

Anatomical context of Ctsa

• The mutant enzyme is correctly compartmentalized in lysosomes and maintains the ability to associate with its activating protein, PPCA [8].
• The deficient phenotype can be corrected by transplanting null mutants with bone marrow from a transgenic line overexpressing human PPCA in erythroid precursor cells [3].
• The cathepsin A precursor has the potential to restore both beta-galactosidase and neuraminidase activities in fibroblasts from patients with galactosialidosis [7].
• Taken together, the data on increase in frequency of macrophages suggests important functions for these cells in both wild type and PPCA -/- mice [9].
• Characterization of cell- and region-specific abnormalities in the epididymis of cathepsin A deficient mice [10].

Associations of Ctsa with chemical compounds

• Cathepsin A/protective protein [3.4.16.5], carboxypeptidase A, is a lysosomal serine protease with structural homology to yeast (Saccharomyces cerevisiae) carboxypeptidase Y [7].
• These results suggest that spinal 5-HT receptors and alpha2-adrenoceptors are involved in the antinociception induced by MPCA and PPCA, but not in that elicited by dipyrone [11].
• Intrathecal (i.t.) administration of methysergide (3 and 10 microg) and yohimbine (3 microg), but not of prazosin (0.3 and 1 microg) prevented the antinociceptive action of MPCA and PPCA (500 micromol/kg, s.c.). Dipyrone-induced antinociception (500 micromol/kg, s.c.) was not affected by methysergide or adrenoceptor antagonists [11].
• Since cathepsin A is also a tumor-associated enzyme, further research is needed to clarify its role and the significance of its inhibition by lactacystin in tumor biology [2].
• Cathepsin A activity was strongly inhibited by Ag+, Hg2+, diisopropylfluorophosphate and p-chloromercuriphenylsulphonic acid [12].

Physical interactions of Ctsa

• Protective protein/cathepsin A (PPCA) is a pleiotropic lysosomal enzyme that complexes with beta-galactosidase and neuraminidase, and possesses serine carboxypeptidase activity [13].

Other interactions of Ctsa

• The pathologic manifestations in patients relate primarily to the severe deficiency of neuraminidase, and the physiological significance of cathepsin A activity remains unclear [6].
• Several lines of evidence indicate that cathepsin A is a multicatalytic enzyme with deamidase and esterase in addition to carboxypeptidase activities [7].

Analytical, diagnostic and therapeutic context of Ctsa

• We have shown by reverse transcription-polymerase chain reaction (RT-PCR) that both parental alleles of Ppgb were expressed in the brain and kidney of 17.5-day-old embryos, 18.5-day-old embryos, and newborn mice [5].

References