2010/04/28

Interacting Pathologies

Workers in Texas and Chile, including Joachin Castilla (who is now at the CIC bioGUNE Institute), have shown a link between the pathological mechanisms of Alzheimer's disease and Prion disease in a mouse model system.

A group of human diseases is associated with the accumulation of misfolded proteins. These diseases tend to develop late in life, strike without warning and are progressive, causing tremendous suffering both to patients and their immediate families. The nervous system is particularly sensitive to such misfolding diseases. The most common dementia, Alzheimer's, is a misfolding disease which affects about 15 million people worldwide. Other dementias include Parkinson's and Huntington's. Current therapies reduce the symptoms of these diseases in the early stages, but do not block disease progression. There is an urgent need to develop effective treatments.

What these progressive dementias share in common with other misfolding disorders, such as Type 2 diabetes, is the accumulation of plaques of protein in the "amyloid" conformation. In each case, the amyloid consists of fibrils of a protein which is a normal component of healthy cells that has become misfolded and insoluble in the disease state, but the amyloid is formed from different proteins in each disease. Once initiated, amyloid fibrils appear to act like a crystal seed onto which more protein can assemble and adopt the amyloid conformation.

The prion diseases share these features with other conformational diseases, but have the unique feature that they are transmissible from one organism to another. Introduction of a prion protein, PrpSc "seed", can initiate the disease process in a new host. Again the incubation periods can be very long, so that prion diseases also tend to appear late in life. These diseases are rare in humans, but underlie Creutzfelt-Jakob disease (CJD) and fatal familial insomnia.

Many proteins adopt their correct, active conformation when synthesized in vitro, but others require the help of protein "chaperones" to adopt such a conformation. The factors that affect growth of amyloid deposits therefore include the protein synthesis and degradation mechanisms, and the presence of the correct chaperones. All these processes must be in balance in a healthy cell, but tend to become less efficient with age. The presence of amyloid fibril seeds may tip the balance and initiate the disease state.

The study by Morales and his colleagues shows that the onset of prion disease symptoms is more rapid in the Alzheimer model mouse strain Tg2576 than in wild-type mice. Critically, if the Tg2576 mice are aged, to the stage when Alzheimer's amyloid is detectable in their brains before inoculation with prions, then the incubation period for prion disease is substantially reduced. In addition, the formation of Alzheimer's amyloid is increased in prion infected mice. These results confirm the observation that Type 2 diabetes and Alzheimer's are risk factors for each other in human disease and that there may be a common mechanism for protein misfolding diseases. It may be that PrpSc and Alz amyloids can cross-seed the accumulation of each other's misfolded proteins. Alternatively, overloading of the chaperone system that ensures correct protein-folding or the misfolded peptide degradation mechanisms might underlie the synergistic effects of these pathologies. In either case, the confirmation that common mechanisms may be underlying the protein misfolding diseases is striking and understanding these mechanism is essential for the development of effective treatments.

-David Gubb