Proteopathy – Diseases caused by Proteins
Reaserach has shown that many neurodengenerative diseases are a result of wrongly folded proteins. In medicine, proteopathy (Proteo- [pref. protein]; -pathy [suff. disease]) refers to a class of diseases in which certain proteins become structurally abnormal, and thereby disrupt the function of cells, tissues and organs of the body. Aggregated proteins are associated with prion**-related illnesses such as Mad Cow Disease (Creutzfeldt-Jakob disease, bovine spongiform encephalopathy) or amyloid-related illnesses such as Alzheimer's, Huntington's and Parkinson's disease. These are either late onset or age onset degenerative diseases and show a multimerization of misfolded proteins into insoluble, cellular aggregates called amyloid fibrils; it is not clear whether the aggregates are the cause or merely a reflection of the loss of protein homeostasis, the balance between synthesis, folding, aggregation and protein turnover. While protein replacement therapy has historically been used to correct the disorders, an emerging approach is to use pharmaceutical chaperones to fold mutated proteins to render them functional.
Micrograph of a section of the cerebral cortex from a patient with Alzheimer's disease, immunostained with an antibody to Aβ (brown), a protein fragment that accumulates in senile plaques and cerebral amyloid angiopathy. 10X objective.
In most proteopathies, a change in 3-dimensional folding (conformation) increases the tendency of a specific protein to bind to itself. In this aggregated form, the protein is resistant to clearance and can interfere with the normal capacity of the affected organs. Only a relatively small number of proteins are linked to proteopathic disorders. For example, proteins that are relatively unstable as monomers (that is, as single, unbound molecules) are more likely to misfold into an abnormal conformation. In nearly all instances, the disease-causing molecular configuration involves an increase in beta-sheet secondary structure of the protein.
The likelihood that proteopathy will develop is increased by certain risk factors that promote the self-assembly of a protein. These include destabilizing changes in the primary amino acid sequence of the protein, post-translational modifications (such as hyperphosphorylation), changes in temperature or pH, an increase in production of a protein, or a decrease in its clearance. Advancing age is a strong risk factor, as is traumatic brain injury. In the aging brain, multiple proteopathies can overlap.
Seeded Induction
Some proteins can be induced to form abnormal assemblies by exposure to diseased proteins, a process called 'seeding' or 'permissive templating'. Ingestion of diseased tissue (nerve tissue from mad cows) is known to be the cause of the prion disease. There is now evidence that other proteopathies can be induced by a similar mechanism, In all of these instances, an aberrant form of the protein itself appears to be the pathogenic agent. In some cases, the deposition of one type of protein can be experimentally induced by aggregated assemblies of other proteins that are rich in β-sheet structure, possibly because of structural complementarily of the protein molecules.
**Prions propagate by transmitting a misfolded protein state. When a prion enters a healthy organism, it induces existing, properly folded proteins to convert into the disease-associated, prion form; the prion acts as a template to guide the misfolding of more proteins into prion form. These newly formed prions can then go on to convert more proteins themselves; this triggers a chain reaction that produces large amounts of the prion form.[7] All known prions induce the formation of an amyloid fold, in which the protein polymerises into an aggregate consisting of tightly packed beta sheets. Amyloid aggregates are fibrils, growing at their ends, and replicating when breakage causes two growing ends to become four growing ends. The incubation period of prion diseases is determined by the exponential growth rate associated with prion replication, which is a balance between the linear growth and the breakage of aggregates.
After reading the article, answer the following questions in complete sentences.
1. What is proteopathy and what causes them?
2. Describe a prion.
3. List four major diseases that are cause (or partially caused) by prion related issues.
4. What is the typical treatment for proteopathy?
5. Explain a new technique for treatment.
6. Describe how most proteopathies occur in the human body.
7. List the risk factors of proteopathy.
8. Describe seeded induction and why/how it may be successful in limiting proteopathies.