Prion Disease

The Role of the Proteasome Degradative Pathway in Prion Disease
2005 Seed Grant
James A. Mastrianni, M.D., Ph.D.
The University of Chicago

The prion diseases are transmissible neurodegenerative disorders linked to the accumulation of an aberrantly folded prion protein (PrP). Current thinking holds that quality control mechanisms within the endoplasmic reticulum (ER), where secretory proteins enter following synthesis, act to either refold or eject misfolded proteins to the cytosol for degradation by a degradative unit known as the proteasome. Recent work supports such a model for prion protein (PrP) (Ma and Lindquist 2001),and dysfunction of this degradative arm is proposed to promote the accumulation of misfolded PrP and the eventual development of prion disease, although this hypothesis is not universally accepted. Transgenic mice that overexpress PrP directly into the cytosolic compartment known as the Tg104 mice, have been generated as a way to model proteasome dysfunction. These mice spontaneously developclinical signs of prion disease at 12 to 14 months of age and on histopathologic exarnlnatlon, there is focal neuronal loss and reactive gliosis within the cerebellar granule cell layer. While these mice demonstrate signs of toxicity from the presence of cytosolic PrP, itis not yet known if the cytosolic PrP that accumulates is a true model of prion disease. The presence of infectivity within the brain tissue from these animals would provide that support. If brain tissue from these mice is truly infectious to other mice, it would confirm that accumulation of cytosolic misfolded PrP can -stimulate the formation of prions. We propose to test whether cytosolic PrP generated in the TgtD4mice, or in cultured cells expressing cytosolicPrP in the absence and presence ofproteasome inhibitors, is truly infectious. We will test infectivity of these samples by the intracerebral inoculation of mice and observe the mice for the development of prion disease. We win compare the onset of disease with that of a standard inoculum of mouse adapted prions from the Rocky Mountain Labs (RML) isolate. This study will help to resolve an important question in prion research, namely, “iscytosolic PrP the origin of infectious prions?” If so, this will implicate dysfunction of the proteasome (perhaps as a result of normal aging) as the initiator of prion disease and will stimulate a new avenue of prion research and options for therapy. Such work will stimulate a new avenue of study and provide support for future NIH funding.
A better understanding of the nature of prion generation is critical for a number of reasons, the most immediate of which is the public health concern of mad cow disease, a threat that continues. For example, the first Japanese patient infected with mad cow disease was recently reported, which is thought to be related to a blood transfusion from another patient with mad cow-related prion disease. Another case related to blood transfusion was reported in the UK 6 months ago. In addition to mad cow disease is chronic wasting disease of deer and elk, a prion disease that affects deer in the wild and is spreading throughout the country. It is not yet clear what risk this disease is to humans. These issues raise the level of concern to better understand these enigmatic diseases. Our studies will help to define the mechanism of prion generation and will greatly assist our efforts to plan and develop new therapies for these diseases. In addition, as noted above, while other neurodegenerative diseases do not demonstrate the transmissibility of prion disease, the biology of a variety of diseases, such as Parkinson, Huntington, Alzheimer, and amyotrophic lateral sclerosis (ALS), overlap significantly with prion biology. What we learn from prion research is often directly transferable to these other neurodegernative diseases, all of which are related to the accumulation of naturally occurring proteins that are misfolded.

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