Robert Sheaff, Ph.D.
University of Minnesota Cancer Center

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.

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