Senior Scholar Award in Aging
Whitehead Institute for Biomedical Research
Investigating the Potential Involvement of Cellular Quality Control Mechanisms and the Mammalian Prion, PrP, in Neurodegenerative Diseases
Aging is invariably associated with reduced neurological function. Moreover, the incidence of acute neurodegenerative disease strongly increases with age. As the average lifespan lengthens due to improvements in medicine and public health, the incidence of devastating neurodegenerative diseases will inevitably rise to become one of the most intractable barriers to living longer, more fulfilling lives.
Neurodegenerative diseases are increasingly recognized as protein folding disorders. In several major neurodegenerative diseases associated with aging, Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD), there is evidence that protein degradation is impaired perhaps by specific misfolded proteins. Our recent research indicates that misfolded prion protein, PrP (the central agent in “Mad Cow Disease” and other transmissible spongiform encephalopathies), accumulates in the cytosol due to inhibition of its degradation.
We propose to test a new hypothesis on the mechanism of neurodegenerative disease progression. Specifically, we suggest that there may be general underlying mechanisms involving the quality control machinery of the cell and the extraordinary toxicity of prion protein, PrP, when it accumulates in the cytosol (normally PrP is located on the cell surface). This accumulation can affect the etiology and severity of neurological diseases typical of the aging process.
If the hypothesis is correct, it will identify PrP as an important therapeutic target and the quality control machinery as an important factor in its toxic affect. We have already established that manipulating PrP mistrafficking can prevent the toxicity of accumulating PrP. Hence, potential therapeutic approaches with PrP have already reached the realm of possibility and could connect with the planned study relatively quickly. A second general mechanism we will investigate is whether amyloid aggregations cause stress to the quality control machinery and thereby trigger a cascade of events that leads to programmed cell death (apoptosis). This possibility was indicated when we expressed PrP in the cytosol causing cells to show symptoms of apoptosis.
If successful, this project would provide crucial, far-reaching information on the etiology of the neurodegenerative diseases. This knowledge would provide potential new avenues for treatment of these devastating diseases.