ABSTRACT
Mammalian cells remove misfolded proteins using various proteolytic systems, including the ubiquitin (Ub)-proteasome system (UPS), chaperone mediated autophagy (CMA) and macroautophagy. The majority of misfolded proteins are degraded by the UPS, in which Ub-conjugated substrates are deubiquitinated, unfolded and cleaved into small peptides when passing through the narrow chamber of the proteasome. The substrates that expose a specific degradation signal, the KFERQ sequence motif, can be delivered to and degraded in lysosomes via the CMA. Aggregation-prone substrates resistant to both the UPS and the CMA can be degraded by macroautophagy, in which cargoes are segregated into autophagosomes before degradation by lysosomal hydrolases. Although most misfolded and aggregated proteins in the human proteome can be degraded by cellular protein quality control, some native and mutant proteins prone to aggregation into beta-sheet-enriched oligomers are resistant to all known proteolytic pathways and can thus grow into inclusion bodies or extracellular plaques. The accumulation of protease-resistant misfolded and aggregated proteins is a common mechanism underlying protein misfolding disorders, including neurodegenerative diseases such as Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), prion diseases and Amyotrophic Lateral Sclerosis (ALS). In this review, we provide an overview of the proteolytic pathways in neurons, with an emphasis on the UPS, CMA and macroautophagy, and discuss the role of protein quality control in the degradation of pathogenic proteins in neurodegenerative diseases. Additionally, we examine existing putative therapeutic strategies to efficiently remove cytotoxic proteins from degenerating neurons.
Subject(s)
Animals , Humans , Alzheimer Disease/drug therapy , Amyloid beta-Peptides/metabolism , Amyotrophic Lateral Sclerosis/drug therapy , Autophagy/drug effects , DNA-Binding Proteins/metabolism , Huntington Disease/drug therapy , Lysosomes/metabolism , Molecular Targeted Therapy , Mutation , Nerve Tissue Proteins/genetics , Neurodegenerative Diseases/drug therapy , Parkinson Disease/drug therapy , PrPSc Proteins/metabolism , Prion Diseases/drug therapy , Proteasome Endopeptidase Complex/metabolism , Proteolysis , Proteostasis Deficiencies/metabolism , Superoxide Dismutase/metabolism , Ubiquitin/metabolism , alpha-Synuclein/metabolism , tau Proteins/metabolismABSTRACT
BACKGROUND: Cathepsin D is an acid optimal protease present in a variety of normal and neoplastic tissues. Cathepsin D is an aspartylendopeptidase which is thought to be important in intracellular processes, such as protein degradation, and cathepsin D may be implicated in intracellular protein turnover. Recent evidence shows that in rabbit alveolar marcrophages, cathepsin D is synthesized as an inactive, membrane associated precursor which is then processed, via an active membrane-associated intermediate form, to an active soluble form of cathepsin D found in lysosomes and endosomes. Antibodies to cathepsin D which are suitable for immunohistochemistry have been available for approximately 20 years although the first immunohistochemical study of cathepsin D as a prognostic factor in breast cancer appeared in 1990. METHOD: The sample in this study consisted of 121 breast cancer's that had been surgically resected. Using the mouse monoclonal antibody (NCL-CDm, Novocastra Laboratories Ltd, UK) specific for the cathepsin D, we performed immunohistochemical staining by ABC methods. We examined the correlations between the expression of cathepsin D and the patient's age, the estrogen receptor status, the tumor size, the lymph node involvement, the staging, the menopausal state, the pathologic grade, the DNA ploidy, and the S-phase fraction. RESULTS: Overall, 53.7% of the patients were positive for cathepsin D. Positive staining did not correlate with age, estrogen receptor status, tumor size, axillary node status, tumor stage, monopausal status, pathologic grade, DNA ploidy, or S-phase fraction. CONCLUSIONS: The expression of cathepsin D by tumor cells was not the only significant prognostic factor of the breast cancer. We need more follow-up studies, and we need exact calculations of the survival rate.
Subject(s)
Animals , Humans , Mice , Antibodies , Breast Neoplasms , Breast , Cathepsin D , DNA , Endosomes , Estrogens , Follow-Up Studies , Immunohistochemistry , Lymph Nodes , Lysosomes , Membranes , Ploidies , Proteolysis , Survival RateABSTRACT
To determine whether the expression of Sialosyl-Tn antigen may have its putative relationship as an established or potentially useful clinicopathologic prognostic parameter in breast cancer, we evaluated 110 patients with invasive breast carcinoma, using formalin-fixed, paraffin-embedded tissue sections. STn antigen was detected by the HB-STn antibody using an avidin-biotin-peroxidase method. The parameters studied were tumor size, nodal status, stage, histologic grade, ER/PR expression, DNA ploidy and S-phase fraction. STn expression was observed in 42 patients (38.2%) with breast cancer. The expression rate of STn was associated with axillary node metastasis. A tendency towards an association between STn expression and tumor size or TNM stage. There was no relationship between STn expression and histologic grade, ER/PR expression, DNA ploidy and S-phase fraction. We conclude that the detection of STn expression may be useful for predicting lymph node metastasis.
Subject(s)
Humans , Breast Neoplasms , Breast , DNA , Lymph Nodes , Neoplasm Metastasis , PloidiesABSTRACT
Mouse monoclonal antibody was used for this study. This study was undertaken to define the prognostic value of the expression of Cathepsin-D in 121 breast cancer patients. The results were as follows: 1) Overall, 53.7% of patients were positive for Cathepsin-D 2) Positive staining did not correlate with age, estrogen receptor status,tumor size, axillary nodal status, tumor stage, menopausal status, pathologic grade, DNA ploidy and S-phase fraction.
Subject(s)
Animals , Humans , Mice , Breast Neoplasms , Breast , DNA , Estrogens , PloidiesABSTRACT
No abstract available.