The function(s) of clusterin may depend upon its topological location. A variety of intracellular... more The function(s) of clusterin may depend upon its topological location. A variety of intracellular "isoforms" of clusterin have been reported but further work is required to better define their identity. The secreted form of clusterin has a potent ability to inhibit both amorphous and amyloid protein aggregation. In the case of amorphous protein aggregation, clusterin forms stable, soluble high-molecular-weight complexes with misfolded client proteins. Clusterin expression is increased during many types of physiological and pathological stresses and is thought to function as an extracellular chaperone (EC). The pathology of a variety of serious human diseases is thought to arise as a consequence of the inappropriate aggregation of specific extracellular proteins (e.g., Abeta peptide in Alzheimer's disease and beta(2)-microglobulin in dialysis-related amyloidosis). We have proposed that together with other abundant ECs (e.g., haptoglobin and alpha(2)-macroglobulin), clusterin forms part of a previously unknown quality-control (QC) system for protein folding that mediates the recognition and disposal of extracellular misfolded proteins via receptor-mediated endocytosis and lysosomal degradation. Characterizing the mechanisms of this extracellular QC system will thus have major implications for our understanding of diseases of this type and may eventually lead to the development of new therapies.
The function(s) of clusterin may depend upon its topological location. A variety of intracellular... more The function(s) of clusterin may depend upon its topological location. A variety of intracellular "isoforms" of clusterin have been reported but further work is required to better define their identity. The secreted form of clusterin has a potent ability to inhibit both amorphous and amyloid protein aggregation. In the case of amorphous protein aggregation, clusterin forms stable, soluble high-molecular-weight complexes with misfolded client proteins. Clusterin expression is increased during many types of physiological and pathological stresses and is thought to function as an extracellular chaperone (EC). The pathology of a variety of serious human diseases is thought to arise as a consequence of the inappropriate aggregation of specific extracellular proteins (e.g., Abeta peptide in Alzheimer's disease and beta(2)-microglobulin in dialysis-related amyloidosis). We have proposed that together with other abundant ECs (e.g., haptoglobin and alpha(2)-macroglobulin), clus...
The pathologies of many serious human diseases are thought to develop from the effects of intra- ... more The pathologies of many serious human diseases are thought to develop from the effects of intra- or extracellular aggregates of non-native proteins. Inside cells, chaperone and protease systems regulate protein folding; however, little is known about any corresponding mechanisms that operate extracellularly. The identification of these mechanisms is important for the development of new disease therapies. This review briefly discusses
The maintenance of the levels and correct folding state of proteins (proteostasis) is a fundament... more The maintenance of the levels and correct folding state of proteins (proteostasis) is a fundamental prerequisite for life. Life has evolved complex mechanisms to maintain proteostasis and many of these that operate inside cells are now well understood. The same cannot yet be said of corresponding processes in extracellular fluids of the human body, where inappropriate protein aggregation is known to underpin many serious diseases such as Alzheimer's disease, type II diabetes and prion diseases. Recent research has uncovered a growing family of abundant extracellular chaperones in body fluids which appear to selectively bind to exposed regions of hydrophobicity on misfolded proteins to inhibit their toxicity and prevent them from aggregating to form insoluble deposits. These extracellular chaperones are also implicated in clearing the soluble, stabilized misfolded proteins from body fluids via receptor-mediated endocytosis for subsequent lysosomal degradation. Recent work also raises the possibility that extracellular chaperones may play roles in modulating the immune response. Future work will better define the in vivo functions of extracellular chaperones in proteostasis and immunology and pave the way for the development of new treatments for serious diseases.
A large body of literature suggests that amyotrophic lateral sclerosis (ALS) pathology is intimat... more A large body of literature suggests that amyotrophic lateral sclerosis (ALS) pathology is intimately linked with neuroinflammation, specifically activation and recruitment of microglia and astrocytes. The actual cause of gliosis is unclear. Extracellular Cu/Zn superoxide dismutase (SOD1) has recently been shown to activate microglia in a CD14 dependant mechanism providing one potential pathway by which glial cells become activated. As protein inclusions are thought to be an important part of ALS pathology and are associated with all forms of ALS, we sought to determine if aggregated SOD1 would activate microglia. Recombinant SOD1 was aggregated and this, or monomeric forms of SOD1 were then added to EOC.13 microglial cells or primary microglial cells in culture. Although monomeric mutant SOD1 has been shown to promote microglial activation in the past, we found that aggregated SOD1 was able to much more efficiently activate microglia in culture when compared with the unaggregated form of mutant SOD1. In addition to CD14 dependant pathways, aggregated SOD1 also bound to the surface of glial cells and was internalized in a lipid raft and scavenger receptor dependent manner. We have for the first time shown that aggregated mutant SOD1 potently activates microglia. These results suggest that there may be a potential link between protein aggregation and microglial activation in ALS.
Dissociation of superoxide dismutase 1 dimers is enhanced by glutathionylation, although the diss... more Dissociation of superoxide dismutase 1 dimers is enhanced by glutathionylation, although the dissociation constants reported to date are imprecise. We have quantified the discreet dissociation constants for wild-type superoxide dismutase 1 and six naturally occurring sequence variants, in their unmodified and glutathionylated forms, at the ratios expressed. Unmodified superoxide dismutase 1 variants that shared similar dissociation constants with SOD1(WT) had disproportionately increased dissociation constants when glutathionylated. This defines a key role for glutathionylation in superoxide dismutase 1 associated familial amyotrophic lateral sclerosis.
Optimal debulking followed by chemotherapy is the standard treatment of managing late-stage ovari... more Optimal debulking followed by chemotherapy is the standard treatment of managing late-stage ovarian cancer, but chemoresistance is still a major problem. In this study, we compared expression profiles of primary tumor tissue from five long-term (>8 years) and five short-term (<2 years) ovarian cancer survivors and identified clusterin as one of the genes that were significantly up-regulated in short-term survivors. We then evaluated the prognostic significance of clusterin and its possible correlation with chemoresistance in ovarian cancer by immunohistostaining of clusterin in 62 tumor samples from patients with stage III, high-grade serous ovarian cancer. After adjusting for debulking status and age, Cox regression analyses showed that high levels of clusterin expression correlate with poor survival (hazard ratio, 1.07; 95% confidence interval, 1.002-1.443; P = .04). We also investigated clusterin in paclitaxel resistance by modulating the endogenous clusterin expression in ...
The function(s) of clusterin may depend upon its topological location. A variety of intracellular... more The function(s) of clusterin may depend upon its topological location. A variety of intracellular &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;isoforms&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; of clusterin have been reported but further work is required to better define their identity. The secreted form of clusterin has a potent ability to inhibit both amorphous and amyloid protein aggregation. In the case of amorphous protein aggregation, clusterin forms stable, soluble high-molecular-weight complexes with misfolded client proteins. Clusterin expression is increased during many types of physiological and pathological stresses and is thought to function as an extracellular chaperone (EC). The pathology of a variety of serious human diseases is thought to arise as a consequence of the inappropriate aggregation of specific extracellular proteins (e.g., Abeta peptide in Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease and beta(2)-microglobulin in dialysis-related amyloidosis). We have proposed that together with other abundant ECs (e.g., haptoglobin and alpha(2)-macroglobulin), clusterin forms part of a previously unknown quality-control (QC) system for protein folding that mediates the recognition and disposal of extracellular misfolded proteins via receptor-mediated endocytosis and lysosomal degradation. Characterizing the mechanisms of this extracellular QC system will thus have major implications for our understanding of diseases of this type and may eventually lead to the development of new therapies.
The function(s) of clusterin may depend upon its topological location. A variety of intracellular... more The function(s) of clusterin may depend upon its topological location. A variety of intracellular "isoforms" of clusterin have been reported but further work is required to better define their identity. The secreted form of clusterin has a potent ability to inhibit both amorphous and amyloid protein aggregation. In the case of amorphous protein aggregation, clusterin forms stable, soluble high-molecular-weight complexes with misfolded client proteins. Clusterin expression is increased during many types of physiological and pathological stresses and is thought to function as an extracellular chaperone (EC). The pathology of a variety of serious human diseases is thought to arise as a consequence of the inappropriate aggregation of specific extracellular proteins (e.g., Abeta peptide in Alzheimer's disease and beta(2)-microglobulin in dialysis-related amyloidosis). We have proposed that together with other abundant ECs (e.g., haptoglobin and alpha(2)-macroglobulin), clus...
The pathologies of many serious human diseases are thought to develop from the effects of intra- ... more The pathologies of many serious human diseases are thought to develop from the effects of intra- or extracellular aggregates of non-native proteins. Inside cells, chaperone and protease systems regulate protein folding; however, little is known about any corresponding mechanisms that operate extracellularly. The identification of these mechanisms is important for the development of new disease therapies. This review briefly discusses
The maintenance of the levels and correct folding state of proteins (proteostasis) is a fundament... more The maintenance of the levels and correct folding state of proteins (proteostasis) is a fundamental prerequisite for life. Life has evolved complex mechanisms to maintain proteostasis and many of these that operate inside cells are now well understood. The same cannot yet be said of corresponding processes in extracellular fluids of the human body, where inappropriate protein aggregation is known to underpin many serious diseases such as Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease, type II diabetes and prion diseases. Recent research has uncovered a growing family of abundant extracellular chaperones in body fluids which appear to selectively bind to exposed regions of hydrophobicity on misfolded proteins to inhibit their toxicity and prevent them from aggregating to form insoluble deposits. These extracellular chaperones are also implicated in clearing the soluble, stabilized misfolded proteins from body fluids via receptor-mediated endocytosis for subsequent lysosomal degradation. Recent work also raises the possibility that extracellular chaperones may play roles in modulating the immune response. Future work will better define the in vivo functions of extracellular chaperones in proteostasis and immunology and pave the way for the development of new treatments for serious diseases.
A large body of literature suggests that amyotrophic lateral sclerosis (ALS) pathology is intimat... more A large body of literature suggests that amyotrophic lateral sclerosis (ALS) pathology is intimately linked with neuroinflammation, specifically activation and recruitment of microglia and astrocytes. The actual cause of gliosis is unclear. Extracellular Cu/Zn superoxide dismutase (SOD1) has recently been shown to activate microglia in a CD14 dependant mechanism providing one potential pathway by which glial cells become activated. As protein inclusions are thought to be an important part of ALS pathology and are associated with all forms of ALS, we sought to determine if aggregated SOD1 would activate microglia. Recombinant SOD1 was aggregated and this, or monomeric forms of SOD1 were then added to EOC.13 microglial cells or primary microglial cells in culture. Although monomeric mutant SOD1 has been shown to promote microglial activation in the past, we found that aggregated SOD1 was able to much more efficiently activate microglia in culture when compared with the unaggregated form of mutant SOD1. In addition to CD14 dependant pathways, aggregated SOD1 also bound to the surface of glial cells and was internalized in a lipid raft and scavenger receptor dependent manner. We have for the first time shown that aggregated mutant SOD1 potently activates microglia. These results suggest that there may be a potential link between protein aggregation and microglial activation in ALS.
Dissociation of superoxide dismutase 1 dimers is enhanced by glutathionylation, although the diss... more Dissociation of superoxide dismutase 1 dimers is enhanced by glutathionylation, although the dissociation constants reported to date are imprecise. We have quantified the discreet dissociation constants for wild-type superoxide dismutase 1 and six naturally occurring sequence variants, in their unmodified and glutathionylated forms, at the ratios expressed. Unmodified superoxide dismutase 1 variants that shared similar dissociation constants with SOD1(WT) had disproportionately increased dissociation constants when glutathionylated. This defines a key role for glutathionylation in superoxide dismutase 1 associated familial amyotrophic lateral sclerosis.
Optimal debulking followed by chemotherapy is the standard treatment of managing late-stage ovari... more Optimal debulking followed by chemotherapy is the standard treatment of managing late-stage ovarian cancer, but chemoresistance is still a major problem. In this study, we compared expression profiles of primary tumor tissue from five long-term (>8 years) and five short-term (<2 years) ovarian cancer survivors and identified clusterin as one of the genes that were significantly up-regulated in short-term survivors. We then evaluated the prognostic significance of clusterin and its possible correlation with chemoresistance in ovarian cancer by immunohistostaining of clusterin in 62 tumor samples from patients with stage III, high-grade serous ovarian cancer. After adjusting for debulking status and age, Cox regression analyses showed that high levels of clusterin expression correlate with poor survival (hazard ratio, 1.07; 95% confidence interval, 1.002-1.443; P = .04). We also investigated clusterin in paclitaxel resistance by modulating the endogenous clusterin expression in ...
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