Research in Progress

HD and Other Neurodegenerative Disorders

Prion-Related Neurodegenerative Disease

Simply stated, prions are infectious proteins. It seems odd to think of proteins as pathogens that can cause the degeneration of the central nervous system, but prions may be the culprit behind several neurodegenerative diseases, including several forms of Creutzfeldt-Jakob disease (CJD). Studying prion-related disease may give insight into possible treatments for Alzheimer’s, Huntington’s, and Parkinson’s disease. (For a comparison of Alzheimer’s, HD, and Parkinson’s, click here.)

In healthy mammals, the nerve cells contain the normal prion protein. This protein can be readily digested by proteases (enzymes that break down proteins) and can be degraded and destroyed by heat and certain chemicals. However, in mammals that have a transmissible spongiform encephalopathy (TSE) -a family of human and animal diseases characterized by spongy deterioration of the brain with severe and fatal neurological symptoms- the infected nerve cells contain the abnormal form of the prion protein. The prion protein has some unusual characteristics: it is insoluble, infectious even at high temperatures, and is almost indestructible (thus, it cannot be fully broken down by proteases). The normal and abnormal prion proteins differ only in their three-dimensional structures (see diagram below). The normal protein is composed mostly of coiled alpha helices, whereas the abnormal protein consists mostly of flat beta sheets. Prion-related disease occurs when the normal prion protein is somehow unfolded and refolded into the abnormal, disease-causing form when it interacts with a prion molecule. Once the normal protein has undergone this transformation, it can then transform other normal protein molecules into the mutant form, and a domino effect begins. Soon the brain is filled with deposits of the insoluble, mutant form of the protein.

Fig. AE-8 to AE-10: Protein structure

1. Primary structure (linear sequence of amino acids):
   
   
   - Glu - Ala - Thr - Val - Asp - Pro - Gly -
2. Secondary structure (conformations of linear chain):
   
   
   
   alpha helices              beta sheet
3. Tertiary structure (three-dimensional, fully folded chain):
   
   
   
4. Prion protein tertiary structure:
   
   
   
   normal prion protein                        abnormal prion protein

Scrapie is a common TSE found in sheep and goats. Bovine spongiform encephalopathy (BSE), or mad cow disease, is a form of TSE that affects cattle. People who consume infected meat are at risk for the human form of mad cow disease, new-variant Creutzfeldt-Jakob disease (nvCJD). This form of CJD strikes people between 16 and 39 old, whereas classic CJD generally affects people over 50 years old. Familial Creutzfeldt-Jakob (fCJD) disease is caused by inherited mutations in the gene that specifies the genetic code for the normal prion protein. Sporadic Creutzfeldt-Jakob (sCJD) disease is caused by the mutation or spontaneous conversion of the normal to the abnormal form of the prion protein.

What is the connection between prion-related diseases and other neurodegenerative disorders, including HD? Almost all neurodegenerative diseases are the result of malfunctioning proteins in nerve cells or an inability to process these proteins, causing them to build up to dangerous levels in the brain. The onset of a particular neurodegenerative disease depends on the type of protein that is not processed correctly.

To treat both prion-related and other neurodegenerative diseases, researchers are trying to develop drugs that target the buildup of proteins: beta-amyloid plaques in Alzheimer’s and CJD and huntingtin protein aggregation in HD. Both beta-amyloid plaques and huntingtin aggregation are similar ways of clogging cell machinery in the nerve cells.

For background information on prion-related and other neurodegenerative diseases, please click here.

Last Modified: 04/12/2007

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