Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Beta-hexosaminidase (Hex) is a lysosomal enzyme that exists as two major isoenzymes: Hex A (subunit structure, alphabeta) and Hex B (betabeta). The presence of Hex in the testis and epididymis suggests important roles for the enzyme and its substrates in male fertility and reproductive functions. Disruption of the Hexb gene encoding the beta-subunit of Hex has led to the generation of a mouse model of human Sandhoff disease that survives to adulthood, enabling us to analyze the effects of Hex A and Hex B deficiency on epithelial cellular morphology of the male reproductive tract. At 1 and 3 months of age, the testes, efferent ducts, and epididymides of Hex-deficient (Hexb -/-) and wild-type (Hexb +/+) mice were perfuse fixed and analyzed by routine light and electron microscopy (LM and EM, respectively) as well as with immunocytochemistry employing antibodies to lysosomal proteins. In the testis, the morphological appearance and topographical arrangement of the cell types of the seminiferous epithelium of Hexb -/- mice were similar to those of wild-type animals at both ages. Both Sertoli and germ cells appeared to be unaffected. However, at both ages, myoid cells and macrophages showed an increased number of lysosomes in their cytoplasm as compared with the number seen in controls. The epithelial cells of the efferent ducts also showed an accumulation of lysosomes that increased with age as compared with controls. Principal cells of the entire epididymis revealed an increase in the size and number of lysosomes at 1 month of age as compared with those of controls, and by 3 months, these lysosomes often filled the supranuclear and basal regions of the cells. Narrow cells of the distal initial segment and intermediate zone, normally slender cells showing several lysosomes, became greatly enlarged and entirely filled with lysosomes in Hexb -/- mice. Clear cells of the caput, corpus, and cauda regions also showed a progressive increase in the size and number of lysosomes with age as compared with controls; the clear cells of the mutant mice were often enlarged and at times bulged into the lumen. Some basal cells of each epididymal region in Hexb -/- mice were similar to controls at 1 and 3 months, showing few lysosomes, while others showed an accumulation of lysosomes. Lysosomes of all affected epithelial cells were of varying sizes, but many large ones were present, apparently resulting from lysosomal fusion. Although pale stained, their identification as lysosomes was confirmed by EM immunocytochemistry with anti-cathepsin D and anti-Hex A antibodies. Predominantly in the proximal initial segment, large, pale cellular aggregates were noted in the LM analysis at the base of the epithelium, which by EM analysis were identified as belonging to two different cell types, narrow cells and halo cells. Taken together, these data reveal an increase in the size and number of lysosomes in all epithelial cell types lining the efferent ducts and entire epididymis as well as in myoid cells and macrophages of the testis. In the light of data showing epididymal defects restricted predominantly to the initial segment in Hexa -/- (Hex A-deficient) mice, our data on the Hexb -/- mice demonstrate a major role for Hex that can be fulfilled by either Hex A or Hex B in the epididymis.
 ...
PMID:I. Abnormalities in cells of the testis, efferent ducts, and epididymis in juvenile and adult mice with beta-hexosaminidase A and B deficiency. 1059 18

Beta-hexosaminidase (Hex) is a lysosomal enzyme that exists as two isoenzymes: Hex A (subunit structure alphabeta) and Hex B (betabeta). Its presence in the testis and epididymis suggests important roles for Hex and its substrates in male fertility and reproductive functions. Disruption of the Hexa gene encoding the alpha-subunit of Hex has led to the generation of a mildly affected mouse model of human Tay-Sachs disease, allowing us the opportunity to analyze the effects of isolated Hex A deficiency on epithelial cellular morphology of the male reproductive tract. At 5 weeks and at 3, 5, and 12 months, the testes, efferent ducts and epididymides of Hex A-deficient (Hexa -/-) and wild-type (Hexa +/+) mice were perfuse fixed and analyzed by routine light and electron microscopy as well as with immunocytochemistry employing antibodies to lysosomal enzymes. In the testis, the seminiferous epithelium of Hexa -/- mice appeared comparable to that of wild-type mice in appearance and topographical arrangement of its cell types at all ages examined. Also, no differences were noted for the efferent ducts. In contrast, there were striking abnormalities in the epididymides of the mutant mice; however, the abnormalities were mainly restricted to the initial segment and intermediate zone. Principal cells of these regions at 5 weeks showed a dramatic increase in the number of lysosomes as compared with those from wild-type animals, and this progressed with increasing age. Furthermore, unlike the few small lysosomes present in wild-type mice, those of Hexa -/- mice were at times enlarged and often filled the supranuclear and basal regions of these cells. In the light microscope, large, dense cellular aggregates were noted at the base of the epithelium in the proximal initial segment that corresponded in the electron microscope to two different cell types, both of which increased in size with age. One aggregate was considered to belong to narrow cells on the basis of the presence of numerous cup-shaped vesicles characteristic of these cells; they appeared to be dislocated from the upper half of the epithelium. In the distal initial segment and intermediate zone, narrow cells were readily identified, but rather than being slender as in the control animals, they were greatly enlarged and filled with pale lysosomes in mutant mice. The second type of cellular aggregate noted in the proximal initial segment corresponded to halo cells. They contained numerous small and large lysosomes and small, Golgi-related, dense, core granules characteristic of halo cells. On the basis of the large size of these cells, they appeared to be actively internalizing substances from the intercellular space. In contrast, principal and clear cells of the caput, corpus, and cauda regions did not appear to show a significant increase in number or size of lysosomes as compared with those of wild-type animals. All structures identified as lysosomes in the various cell types were immunoreactive for cathepsin D. The present data thus reveal that isolated Hex A deficiency results in region- and cell-specific abnormalities in the epididymis but in no apparent abnormalities in the testis or efferent ducts. Specific roles for Hex A that cannot be compensated for by other isozymes of Hex appear to exist within lysosomes of epithelial cells predominantly of the initial segment and intermediate zone. Taken together, the results also suggest that the inability to degrade endocytosed substrates normally acted upon by Hex A in lysosomes of principal and narrow cells leads to their accumulation, eventual fusion, and increased size.
 ...
PMID:II. Characterization and development of the regional- and cellular-specific abnormalities in the epididymis of mice with beta-hexosaminidase A deficiency. 1059 19