On Prions Proteasomes and Mad Cows

The ability of a cell to degrade misfolded proteins, or discard proteins which are no longer useful is essential to the integrity of the cell.  These unwanted proteins can occur or develop naturally, as they may be the product of errors in transcription, mutation, failure to fold correctly, or spontaneous degeneration.  The normal pathway responsible for the effective removal of abnormal proteins is the ubiquitin-proteasome pathway, which utilizes a protein specific tagging system facilitated by ubiquitin, having proteasome degrade the enzyme.  Upon onset, many diseases are identified to posses attributes which increase the amounts of ubiquitin tagged proteins that have not been degraded, or an increase in untagged, and abnormal proteins indicating a failure in the ubiquitin proteasome system entirely.  The diseases associated are cystic fibrosis, amyotrophic lateral sclerosis, Parkinson’s, Lewy-body dementia, Huntington’s disease, and Alzheimer’s.

The mechanism by which these proteins inhibit adequate function in cells remains unclear, yet it is assumed that the proteolytic system is somehow inhibited to allow the buildup of these amyloid proteins. Kristiansen et al has reported evidence that a form of prion disease may be caused by an inhibition of the 26S proteasome. The diseases typically associated are spongiform encephalopathy, creutzfeldt-jacob syndrome, and kuru. These diseases are caused by a toxic prion protein which changes the conformation of the proteasome responsible for degrading abnormal proteins. When this occurs the function of three of the processes associated with the proteasome are inhibited.  It is shown that cells have the ability to regenerate normal proteasome activity if the toxic prion is removed.

The ubiquitin-proteasome pathway has shown to be an integral component of cell signaling networks, and metabolic pathways.  For that reason it has been the selected target of the anticancer drug bortezomib, which is widely used for treatment of Melanoma. This is the target of this drug as the cancer seems to be widely dependent upon proteasomes for survival. It does not inhibit neural function however since it does not cross the blood brain barrier.


N Engl J Med 2007; 357:1150-1152September 13, 2007

1 thought on “On Prions Proteasomes and Mad Cows”

  1. Solid analysis of a system that is not yet totally understood yet is still vastly important in regards to physiological function. You explained the functions of these proteins well and you talked about what happens when this system becomes dysfunctional. I found it interesting that they have developed drugs to treat conditions associated with this system, as before I read this article I was under the impression that diseases of that nature were untreatable. One critique is that, based on the title of the post, I thought you were going to talk specifically about mad cow disease, which is always an interesting topic. But hey still a cool read.

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