The aggregation of misfolded proteins is a feature of most neurodegenerative conditions: amyloid-β and tau in Alzheimer's disease, α-synuclein in Parkinson's disease, and so forth. These and a few more of the countless proteins present in the body can become altered, such as via misfolding, in ways that encourage other molecules of the same protein to also alter, forming structures of linked, harmful proteins that can spread through tissue or from cell to cell. Cells, particularly immune cells, are equipped with a range of mechanisms to identify and break down these problem proteins, but, for reasons that are not fully understood at the detail level, damage outpaces maintenance in the aging brain. Aggregates grow and spread, leaving a trail of cellular dysfunction and death in their wake.
In today's research materials, scientists report on their exploration of a process by which cells ingest and break down misfolded extracellular proteins. Amyloid-β might be the most interesting example of such proteins, given its role in Alzheimer's disease. The researchers note evidence for upregulation of the operation of this maintenance process to reduce the impact of amyloid-β aggregation on brain tissue; we shall see whether this progresses to the point of producing therapies in the years ahead. Certainly researchers are quite interested in upregulating the operation of processes such as autophagy and proteasomal degradation of proteins that are focused on breaking down problem proteins inside cells, so why not also enhance the ability of cells to maintain their surroundings as well?
A number of diseases are believed to be caused by the gradual buildup of misfolded proteins that can aggregate together and damage neurons and other cells in the body. To help prevent this damage, cells have developed numerous quality control systems that recognize misfolded proteins within the cell and either fold them back into their correct shape or else degrade them before they start to aggregate. However, approximately 11% of human proteins exist outside of the cell, where they are subjected to even more stresses that may cause them to misfold. Alzheimer's disease is characterized by aggregates of amyloid-β protein in the extracellular space. Despite this, how aberrant extracellular proteins are degraded remains poorly understood.
A protein called Clusterin can bind to misfolded extracellular proteins and prevent them from aggregating. Researchers discovered that Clusterin can escort misfolded proteins into the cell and deliver them to the cell's garbage-disposal units - the lysosomes - where they can be degraded. The researchers also discovered that, after binding to misfolded proteins, Clusterin enters cells by binding to proteins known as heparan sulfate proteoglycans, which are present on the surface of almost all human cells. Together, Clusterin and heparan sulfate proteoglycans allow many different cell types to internalize and degrade a wide variety of misfolded extracellular proteins.
Intriguingly, the researchers also found that Clusterin and heparan sulfate proteoglycans can import amyloid-β into cells for degradation. Mutations in the gene encoding Clusterin have been linked to an increased risk of developing Alzheimer's disease, and experiments in rats have shown that injecting Clusterin into the brain can prevent amyloid β-induced neurodegeneration. "Our results therefore suggest new avenues for the possible treatment or prevention of disorders such as Alzheimer's disease that are associated with aberrant extracellular proteins."
The accumulation of aberrant proteins leads to various neurodegenerative disorders. Mammalian cells contain several intracellular protein degradation systems, including autophagy and proteasomal systems, that selectively remove aberrant intracellular proteins. Although mammals contain not only intracellular but also extracellular proteins, the mechanism underlying the quality control of aberrant extracellular proteins is poorly understood. Here, using a novel quantitative fluorescence assay and genome-wide CRISPR screening, we identified the receptor-mediated degradation pathway by which misfolded extracellular proteins are selectively captured by the extracellular chaperone Clusterin and undergo endocytosis via the cell surface heparan sulfate (HS) receptor.
Biochemical analyses revealed that positively charged residues on Clusterin electrostatically interact with negatively charged HS. Furthermore, the Clusterin-HS pathway facilitates the degradation of amyloid β peptide and diverse leaked cytosolic proteins in extracellular space. Our results identify a novel protein quality control system for preserving extracellular proteostasis and highlight its role in preventing diseases associated with aberrant extracellular proteins.