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
Query: EC:3.4.23.5 (
cathepsin D
)
4,130
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Maintenance of the appropriate pH in the intracellular vacuolar compartments is essential for normal cell function. Here, we report that
CLN3 protein
, which is associated with the juvenile form of neuronal ceroid lipofuscinosis (JNCL), participates in lysosomal pH homeostasis in human cells. We show that
CLN3 protein
increases lysosomal pH in cultured human embryonal kidney cells, whereas inhibition of
CLN3 protein
synthesis by antisense approach acidifies lysosomal compartments. These changes in lysosomal pH are sufficient to exert a significant biological effect and modify intracellular processing of amyloid-beta protein precursor and
cathepsin D
, model proteins whose metabolism is influenced by the pH of acidic organelles. Mutant CLN3 protein (R334C) that is associated with the classical JNCL phenotype was devoid of biological activities of wild-type
CLN3 protein
. These data suggest that the pathogenesis of juvenile neuronal ceroid lipofuscinosis is associated with altered acidification of lysosomal compartments. Furthermore, our study indicates that
CLN3 protein
affects metabolism of proteins essential for cell functions, such as amyloid-beta protein precursor, implicated in Alzheimer's disease pathogenesis.
...
PMID:CLN3 protein regulates lysosomal pH and alters intracellular processing of Alzheimer's amyloid-beta protein precursor and cathepsin D in human cells. 1092 75
Although the CLN3 gene associated with the disease process in subjects with the juvenile form of neuronal ceroid lipofuscinosis was discovered in 1995, our knowledge of the physiological function of its gene product,
CLN3 protein
, is still incomplete. To gain more insight into the structural properties and function of
CLN3 protein
we studied at present: i) how the naturally occurring point mutations Arg334Cys and Leu101Pro affect the biological properties of
CLN3 protein
, and ii) whether depletion of
CLN3 protein
synthesis by using an antisense approach induces a distinct phenotype in cells of neuronal origin in vitro. Here we report that although both CLN3 mutant proteins are targeted to lysosomes, thus similar to wild-type
CLN3 protein
, they are devoid of the biological activity of wild-type
CLN3 protein
such as its effect on lysosomal pH or intracellular processing of amyloid-beta protein precursor and
cathepsin D
in vitro. The Leu101Pro mutation affected significantly the maturation and stability of
CLN3 protein
. The Arg334Cys mutation influenced mildly the maturation and turnover of
CLN3 protein
, but at the same time abolished the function of
CLN3 protein
in vitro, which suggests that the Arg334 may constitute a part of the active site of
CLN3 protein
. In addition, we show that depletion of
CLN3 protein
synthesis in human neuroblastoma cells in vitro induces outgrowth of long cellular processes and formation of cellular aggregates and affects the viability of these cells. This finding suggests that
CLN3 protein
is implicated in biological processes associated with the differentiation of cells of neuronal origin.
...
PMID:CLN3 disease process: missense point mutations and protein depletion in vitro. 1158 14
