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, posttranslational 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.