Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.23.5 (cathepsin D)
4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The endosomal lysosomal system might play a role in Alzheimer's disease, but its impact in major depression is unknown. The expression of the cation-dependent mannose 6-phosphate receptor (CD-MPR) is increased in Alzheimer's disease and the CD-MPR gene is located next to a region on chromosome 12 possibly linked to Alzheimer's disease. We investigated a C/T polymorphism in the CD-MPR gene in 188 Alzheimer's disease patients, in a control sample of 193 patients with major depression, as hospitalized controls, and in 259 healthy controls. We examined the interaction of the CD-MPR polymorphism with the putative risk factor for Alzheimer's disease, the cathepsin D T-allele. No significant association of the CD-MPR C-allele with Alzheimer's disease was observed. However, exploratory data analysis revealed an increased frequency of the CD-MPR C-allele in patients with major depression; thus, the C-allele may be a risk factor for depression. Gene location and function of the CD-MPR suggest an involvement in Alzheimer's disease; however, we could not find an association of the CD-MPR polymorphism with Alzheimer's disease. Since exploratory data suggest an involvement of the endosomal lysosomal system in major depression, further studies are warranted to investigate the biological role of the CD-MPR in major depression.
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PMID:Putative association of polymorphism in the mannose 6-phosphate receptor gene with major depression and Alzheimer's disease. 1516 96

Cathepsin D (CTSD) is an intracellular aspartyl protease, which is active in the endosomal/lysosomal system. 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. A functional polymorphism in exon 2 of the cathepsin D gene (C-->T, Ala224Val) has recently been reported to increase the risk for AD in some of the Caucasian populations, with a significant overrepresentation of the T allele, but these reports have not been universally duplicated. We performed an association study between CTSD polymorphism and AD in 156 sporadic AD patients and 183 controls of Chinese Han ethnicity. Our data revealed that the distribution of CTSD genotypes and alleles was similar in patients and controls. No direct association was found between CTSD polymorphism and AD risk. There might be a weak synergistic interaction between CTSD T and APOEepsilon4 allele in increasing the risk for developing AD.
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PMID:Association between cathepsin D polymorphism and Alzheimer's disease in a Chinese Han population. 1521 Oct 64

The deposition of beta-amyloid peptides (A beta42 and A beta40) in neuritic plaques is one of the hallmarks of Alzheimer's disease (AD). A beta peptides are derived from sequential cleavage of amyloid precursor protein (APP) by beta- and gamma-secretases. BACE-1 has been shown to be the major beta-secretase and is a primary therapeutic target for AD. In this article, two novel assays for the characterization of BACE-1 inhibitors are reported. The first is a sensitive 96-well HPLC biochemical assay that uses a unique substrate containing an optimized peptide cleavage sequence, NFEV, spanning from the P2-P2' positions This substrate was processed by BACE-1 approximately 10 times more efficiently than was the widely used substrate containing the Swedish (NLDA) sequence. As a result, the concentration of the enzyme required for the assay can be as low as 100 pM, permitting the evaluation of inhibitors with subnanomolar potency. The assay has also been applied to related aspartyl proteases such as cathepsin D (Cat D) and BACE-2. The second assay is a homogeneous electrochemiluminescence assay for the evaluation of BACE-1 inhibition in cultured cells that assesses the level of secreted amyloid EV40_NF from HEK293T cells stably transfected with APP containing the novel NFEV sequence. To illustrate the use of these assays, the properties of a potent, cell-active BACE-1 inhibitor are described.
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PMID:Biochemical and cell-based assays for characterization of BACE-1 inhibitors. 1595 91

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. We studied CTSD exon 2 (C224T) and apolipoprotein E (APOE) genotype frequencies in 168 AD patients and 218 age-matched healthy controls from Southern Italy. 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. Furthermore, comparing our results with the findings from other European populations, the CTSD*T allele frequency showed a statistically significant increasing trend from Northern to Southern regions of Europe in AD patients and controls (z=2.51, p<.01; z=4.02, p<.001, respectively), with a concomitant inverse trend for CTSD*C allele frequency. 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.
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PMID:The cathepsin D gene exon 2 (C224T) polymorphism and sporadic Alzheimer's disease in European populations. 1612 1

The aim of our work was to detect minor loci acting as Alzheimer's disease (AD) genetic markers. We divided 206 AD patients and 186 individuals as controls into six age at onset/age-dependent groups. We studied polymorphisms of the genes of apolipoprotein E (APOE) and its promoter, cathepsin D, butyrylcholinesterase, cystatin C, methionine synthase, and cystathionine beta-synthase. Our results demonstrated that data analysis according to age at onset allows the detection of minor genetic risk factors for AD. Thus, the Th1/E47cs-G allele was an independent AD risk factor after 80 years, whereas the catD-T, BChE-K, CBS-844ins68, and CBS-VNTR 19 alleles are independent AD risk factors after 75 years. On the other hand, the CST3-A allele was an independent AD risk factor before 60 years while the CBS-VNTR allele 21 was an independent AD risk factor before 64 years. In contrast, the MS-AA genotype was an AD risk factor unrelated to age at onset. In conclusion, two main tasks remain to be accomplished to facilitate early detection of people at risk of developing AD: (1) the establishment of common criteria to carry out association studies for different genetic markers, including the introduction of AD age at onset as a crucial variable in each study, and (2) the definition of global and population-specific genetic markers for each age at onset AD subgroup.
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PMID:Age at onset: an essential variable for the definition of genetic risk factors for sporadic Alzheimer's disease. 1639

Genetic variations represent major risk factors for Alzheimer's disease (AD). While familial early onset AD is associated with mutations in the amyloid precursor protein and presenilin genes, only the e4 allele of the apolipoprotein E (APOE) gene has so far been established as a genetic risk factor for late onset familial and sporadic AD. It has been suggested that the C-->T (224Ala-->Val) transition within exon 2 of the cathepsin D gene (CTSD) might represent a risk factor for late onset AD. The objective of this study was to investigate whether possession of the CTSD exon 2 T allele increases the risk of developing AD, and to determine whether this modulates the amyloid pathology of the disease in conjunction with, or independent of, the APOE e4 allele. Blood samples were obtained from 412 patients with possible or probable AD and brain tissues from a further 148 patients with AD confirmed by postmortem examination. CTSD and APOE genotyping were performed by PCR on DNA extracted from blood, or from frontal cortex or cerebellum in the postmortem cases. Pathological measures of amyloid beta protein (Abeta), as plaque Abeta40 and Abeta42(3) load and degree of cerebral amyloid angiopathy were made by image analysis or semiquantitative rating, respectively. CTSD genotype frequencies in AD were not significantly different from those in control subjects, nor did these differ between cases of early or late onset AD or between younger and older controls. There was no gene interaction between the CTSD T and APOE e4 alleles. The amount of plaque Abeta40 was greater in patients carrying the CTSD T allele than in non-carriers, and in patients bearing APOE e4 allele compared with non-carriers. Possession of both these alleles acted synergistically to increase levels of plaque Abeta40, especially in those individuals who were homozygous for the APOE e4 allele. Possession of the CTSD T allele had no effect on plaque Abeta42(3) load or degree of CAA. Possession of the CTSD T allele does not increase the risk of developing AD per se, but has a modulating effect on the pathogenesis of the disorder by increasing, in concert with the APOE e4 allele, the amount of Abeta deposited as senile plaques in the brain in the form of Abeta40.
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PMID:Genetic associations between cathepsin D exon 2 C-->T polymorphism and Alzheimer's disease, and pathological correlations with genotype. 1654 33

The multiple polymorphisms contributing to Alzheimer disease (AD) have been difficult to identify. Three essentially sufficient risk sets were found using a fuzzy latent classification statistical model; that is, grade-of-membership analysis, and genotypes for APOE, APOCI, LDLr, cystatin C, and cathepsin D (180 cases, 120 controls). These were: (a) CST3:GA and CTSD:CT; (b) APOE44 and LDLr8:GG and LDLr13:TT; and (c) APOE34 and LDLr13:TC. Consonance with one of the groups and high aggregate membership carried >800-fold elevated risk for AD. The absence of these combinations defined low risk. APOE3/- with heterozygous promoter and receptor genotypes predicted long life without dementia.
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PMID:Membership in genetic groups predicts Alzheimer disease. 1660 2

The lysosomal protease cathepsin D (CtsD, EC 3.4.23.5; gene, CTSD) has been associated with Alzheimer disease (AD) due to its cerebral expression being increased early in the course of AD; additionally, a CTSD exon 2 polymorphism (rs17571; NT_009237.17:g.569834T>C) may confer risk to AD. Functionally, it may be implicated in amyloid precursor protein (APP) processing and tau protein degradation. The objective of this study was to determine whether the CTSD exon 2 polymorphism affects cerebrospinal fluid (CSF), concentrations of beta-amyloid (Abeta42) and tau in two independent samples from Germany (n=73) and Sweden (n=66). Patients carrying the CTSD rs17571-T allele had significantly decreased CSF levels of tau (Munich, p=0.003; Swedish, p=0.029; combined sample, p<0.001), whereas no significant effect was observed on Abeta42 concentrations. Likewise, no significant impact was observed on Mini Mental State Examination (MMSE) scores. The data of both independent samples suggest that the CTSD rs17571 polymorphism does not affect APP processing but shows significant effects on tau processing. The result may corroborate the implication of the lysosomal system in the pathogenesis of AD and is of particular importance if CSF tau is used as a diagnostic biomarker.
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PMID:The cathepsin D rs17571 polymorphism: effects on CSF tau concentrations in Alzheimer disease. 1665 47

Aspartic proteases are receiving considerable attention as potential drug targets in several serious diseases, such as AIDS, malaria, and Alzheimer's disease. These enzymes cleave polypeptide chains, often between specific amino acid residues, but despite the common reaction mechanism, they exhibit large structural differences. Here, the catalytic mechanism of aspartic proteases plasmepsin II, cathepsin D, and HIV-1 protease is examined by computer simulations utilizing the empirical valence bond approach in combination with molecular dynamics and free energy perturbation calculations. Free energy profiles are established for four different substrates, each six amino acids long and containing hydrophobic side chains in the P1 and P1' positions. Our simulations reproduce the catalytic effect of these enzymes, which accelerate the reaction rate by a factor of approximately 10(10) compared to that of the corresponding uncatalyzed reaction in water. The calculations elucidate the origin of the catalytic effect and allow a rationalization of the fact that, despite large structural differences between plasmepsin II/cathepsin D and HIV-1 protease, the magnitude of their rate enhancement is very similar. Amino acid residues surrounding the active site together with structurally conserved water molecules are found to play an important role in catalysis, mainly through dipolar (electrostatic) stabilization. A linear free energy relationship for the reactions in the different enzymes is established that also demonstrates the reduced reorganization energy in the enzymes compared to that in the uncatalyzed water reaction.
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PMID:Catalysis and linear free energy relationships in aspartic proteases. 1678 22

The proteins cathepsin D, encoded by CTSD gene, and alpha2-macroglobulin, encoded by A2M gene, are involved in the biochemical pathway leading to deposition of beta-amyloid. In these proteins two amino acid polymorphisms (CTSD-Ala/Val C-->T and A2M-Ile/Val A-->G) have been associated with an increased risk for Alzheimer's disease (AD), but conflicting results have been reported. We studied the association and the mutual interactions of the CTSD-C/T and A2M-A/G polymorphisms with sporadic AD in 100 patients with late-onset AD and 136 healthy elderly subjects as controls. The CTSD-T allele and the CTSD-C/T genotype are significantly more frequent in AD than in controls. The odds ratio (OR) for CTSD-T subjects is 1.93 [95% confidence interval (CI)=1.01-3.72], and 2.07 (95% CI=1.01-4.21) after adjustment for age, sex and APOE epsilon4+ status, while no significant association was found for the A2M-A/G polymorphism. The coexistence of the CTSD-T with the A2M-G allele synergistically increased the OR for AD to 2.69 (95% CI=1.13-6.34) [2.82 (95% CI=1.12-7.17) after adjustment], and to 3.29 (95% CI=1.33-8.16) if estimated for the allelic combination. Our data suggest that the CTSD-T allele of the CTSD-C/T polymorphism is associated with an increased relative risk for late-onset AD and, more interestingly, the combination of CTSD-T with the A2M-G allele seems to increase this risk.
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PMID:Interaction of CTSD and A2M polymorphisms in the risk for Alzheimer's disease. 1678 55


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