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New Scholar Award in Aging
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Robert
Sheaff,
Ph.D.
University of Minnesota Cancer Center
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A Mechanistic Explanation for the Development of Neurodegenerative Diseases.
Neurodegenerative diseases share many molecular and pathological similarities,
yet no unifying explanation exists to explain how and why they arise. We
propose that defects in a novel biological system underlie development of these
disorders, and will test this hypothesis by investigating a defining feature of
Parkinson's Disease.
Neurodegenerative diseases are characterized by the presence of insoluble
aggregates in brain cells. These aggregates contain abnormal/misfolded protein
(whose identity varies depending on the disease), cytoskeletal components, and
a small protein called ubiquitin. Covalent attachment of ubiquitin to a target
protein is commonly viewed as a "molecular flag" targeting and tethering
selected proteins to the proteasome, where they are unfolded and then
degraded. In this view aggregate formation likely reflects a failed attempt to
degrade aberrant proteins. However, ubiquitin is involved in many processes
other than degradation that are difficult to rationalize with this description.
Our data suggest ubiquitin has a more general role as an integral component of a
novel force application system. This system uses force to accomplish diverse
biological aims, such as protein unfolding or transport. Force application to
target proteins is mediated by cytoskeletal filaments acting on covalently
attached ubiquitin. Thus, ubiquitin functions as a "molecular handle" rather than
a "molecular flag". Such a model necessitates a re-evaluation of aggregate
formation, and suggests disruption of the ubiquitin-mediated application of
force might contribute to development of neurodegenerative diseases. This
hypothesis will be tested by investigating aggregate formation in Parkinson's
Disease, which involves ubiquitin, cytoskeletal components, and a protein
called alpha synuclein. We will use tissue culture cells to determine why
synuclein is ubiquitinated, and how this contributes to its aggregation.
Development of neurodegenerative diseases has been linked to the free radical
theory of aging, but the mechanistic connection remains unclear. We propose
that free radicals disrupt the force application system by inactivating
de-ubiquitinating enzymes, which contain an active site cysteine (an amino acid
highly susceptible to free radical attack). Whether or not age-related
neurodegenerative diseases develop could depend on a number of interacting
factors, such as the initial amount of de-ubiquitinating enzyme activity,
exposure to free radicals, or the efficiency of free radical quenching mechanisms.
Genetic variations in the population--such as loss of one copy of a relevant
gene, or genetic polymorphisms--might predispose certain individuals to the
disease. Thus, susceptibility to disease could perhaps be predicted by
identifying genetic or biochemical variations in de-ubiquitinating enzymes that
exist among the population. Furthermore, reducing the active site cysteine of
de-ubiquitinating enzymes, enzyme replacement, and/or reducing exposure to
free radicals all become attractive therapeutic options for treating these
debilitating illnesses.
Contact
Dr. Sheaff.
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