Protein Mis-Folding Diseases

This post will cover the second topic in our biochemistry unit - protein mis-folding diseases.

The Importance of Protein Folding
 
It has been said that of all the molecules found in organisms, proteins are the most important. Correct folding is essential to the function of a protein because proteins can only work if they are in their natural state. For example, protein folding is important to produce the correct 3D structure of an enzyme's active site, incorrect folding would leave the enzyme useless.

When proteins misfold they can do either one of two things:

• Degradation: Mis-folded proteins are degraded back to peptides by:
• Lysosomal degradation, which is extracellular. Proteins are degraded by lysosomal enzymes.
• Cytosolic degradation, which is intracellular. Misfolded proteins are targeted and are tagged with a chain of ubiquitin molecules. The ubiquitinated proteins are then degraded by a larger multisubunit protein called a proteasome.
• Aggregation: Several misfolded proteins can bind together forming an aggregate that is highly stable causing them to be very difficult for the cell to break down.

Proteasomes degrade ubiquitinated proteins

What Causes Proteins to Misfold?

Several factors can cause proteins to misfold including:

• DNA Mutation
• Stresses during the lifetime of the protein
• Environmental factors such as metals, pesticides and toxins
• Post translational modification. 

Diseases Caused by the Degradation of Misfolded Proteins
When proteins are degraded they become missing in the cell. This can have some severe consequences. An example of a disease caused by the degradation of misfolded proteins is discussed below.

Cystic Fibrosis: 
Cystic Fibrosis is caused by a genetic mutation in a gene which codes for a protein known as CFTR (cyctic fibrosis transmembrane conductance regulator). CFTR controls the passage of chloride ions into and out of the cell which is critical for water balance around the body. In 70-80% of cases of cystic fibrosis, the amino acid phenylalanine in the CFTR protein is missing. This causes the protein to misfold and become degraded by the ubiquinin system. This results in no CFTR proteins in the membrane. Without CFTR sweat is five times saltier, the balance of ions in the blood is altered leading to abnormal heart rythms, Cl ions aren't shuttled into the pancreas causing inflammation, and mucus builds up in the lungs.   


Diseases Caused by the Aggregation of Misfolded Proteins

An example of what might happen when misfolded proteins accumulate in the cell is described below.

Mad Cow Disease / Creutzfeldt-Jakob Disease

Mad Cow disease occurs in animals while the Creutzfeldt-Jakob disease is related and occurs in humans. Together they are known as TSEs - Transmissible Spongiform Encephalopathies. The disease is fatal and leads to a brain disorder which slowly destroys the nervous system. 

Both diseases are caused by the misfolding of a protein called a prion. Prions consist of a single protein and are abnormal variants of proteins that usually occur in cells. Prions are able to convert their normal counterparts into more abnormal forms. This causes the accumulation of insoluble proteins in the cell which leads to cell death and nervous system damage.  


Treatment

At the moment the most promising treatment uses chemical chaperones which are small molecules that bind to a protein, stabilise the folded state and reduce protein misfolding. 


If you have any questions, please feel free to ask by commenting below :)