A mechanism has been identified which is used by the body to clear damaged and misfolded proteins from the extracellular space. The build up of toxic proteins in the extracellular space can lead to cell death, as is the case with neurodegenerative diseases such as Alzheimer’s disease. In the case of Alzheimer’s disease, amyloid β (Aβ) proteins build up and form plaques.
Researchers in Japan have shown that misfolded proteins are cleared from the extracellular space by the chaperone protein Clusterin. The proteins are then degraded inside cells by lysosomes.
The researchers explain that there are many protein control mechanisms inside cells that are used to maintain proteostasis. When misfolded proteins are identified, they are either folded back into the correct shape or they are targeted and degraded before they aggregate.
Previous studies have suggested that Clusterin is the major extracellular chaperone protein in vertebrates and that it binds to stressed proteins in the extracellular space. “We hypothesized that misfolded extracellular proteins may engage chaperone-like proteins that facilitated their degradation through an unidentified cell surface receptor,” wrote the authors in the paper.
The researchers developed a novel quantitative fluorescence assay and genome-wide CRISPR screening to identify what they call a chaperone- and receptor-mediated extracellular protein degradation (CRED) pathway that is used to remove these misfolded proteins from the extracellular space to prevent aggregation. This pathway is used to bring proteins, including Aβ, inside cells for degradation through endocytosis. The process is dependent on heparan sulfate proteoglycans receptors (HS) which are found on the surface of virtually all human cells.
“The Clusterin-misfolded protein complex directly interacted with HS. The interaction is dependent on electrostatic interactions between positively charged residues on Clusterin and negatively charged sulfate on HS,” explained the researchers. The researchers showed that Clusterin selectively binds to Aβ and a range of cytosolic proteins in the extra cellular space and escorts them inside cells for degradation. “We, therefore, think that this pathway is a general extracellular protein quality control system responsible for the clearance of misfolded proteins from diverse tissues and body fluids,” said, Eisuke Itakura, PhD, an assistant professor in the department of biology at Chiba University and first author of the paper.
Past research has linked mutations in the gene that encodes Clusterin with an increased risk of developing Alzheimer’s disease and one study has shown that injecting Clusterin into the brains of rodents helps to prevent the neurodegeneration caused by the buildup of Aβ. If Clusterin could be altered to make it bind to Aβ more easily, it could potentially be used as a treatment for Alzheimer’s disease and other neurodegenerative disorders caused by the build up of toxic proteins in the extracellular space such as Huntington’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease.
You can read more about the research in the paper – Heparan sulfate is a clearance receptor for aberrant extracellular proteins – which was recently published in the Journal of Cell Biology. DOI: 10.1083/jcb.201911126