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Research Grants 2007


To view an abstract, select an author from the vertical list on the left.

2007 Grant - Petrucelli

CHIP, Molecular Chaperones and Tau Biology

Leonard Petrucelli, Ph.D.
Mayo Clinic Jacksonville
Jacksonville, Florida

2007 Investigator-Initiated Research Grant

Proteins consist of long chains of "building blocks" called amino acids that are chemically bound together. These long chains can fold into different conformations. Some of these conformations may be toxic to the cell, while only one or two conformations of a given protein may be beneficial. A common characteristic of most neurodegenerative diseases is the accumulation in neurons of abnormally folded, toxic proteins. In Alzheimer's disease, both beta-amyloid, a small protein fragment, and tau, a much larger protein, can adopt a variety of toxic forms. Preventing these proteins from misfolding is a widely pursued therapeutic strategy.

Leonard Petrucelli, Ph.D., and colleagues plan to tackle tau toxicity by focusing on the cell's natural ability to remove abnormally folded protein. Each cell employs a family of helper proteins called "chaperones" to ensure that newly produced proteins adopt the correct folding pattern. These chaperones work with other proteins to mark misfolded proteins for removal. One of these co-chaperones is CHIP, which stands for carboxy-terminus of Hsc70-interacting protein. CHIP tags unwanted proteins for degradation by a proteasome, a large complex that works like a garbage disposal, chopping proteins up into their constituent amino acids.

The researchers plan to test if inhibiting "heat shock protein 90" (Hsp90), a major chaperone, might relieve tau toxicity. Hsp90 works with other co-chaperones, such as CHIP, to either refold proteins into their proper conformation or direct them down the proteasome degradation pathway. Recently, a series of Hsp90 inhibitors have been developed that prevent the former and stimulate the latter. These inhibitors are currently being developed as cancer therapies because they promote degradation of key cancer proteins. There is also some indication that they can prevent neurodegenerative disease. Petrucelli and colleagues will test these Hsp90 inhibitors in mice that accumulate toxic tau and mimic some of the symptoms of Alzheimer's disease and frontotemporal dementia, a related neurodegenerative disease caused by inherited mutations in the tau gene. Their work could advance a valuable therapeutic approach to treating these disorders.