Henry L. Paulson, M.D., Ph.D.
University of Iowa

Mechanisms of Neuronal Dysfunction and Death in Neurodegenerative Proteinpathies.

As we age, neurons in our brain tend to accumulate abnormal protein. The same process occurs in degenerative diseases of aging such as Alzheimer and Parkinson diseases, but at a much faster rate. Our research aims to identify the various ways that abnormal protein accumulation compromises the neuron in neurodegenerative diseases. Our long term objective is to extend these findings to the study of normal aging in the central nervous system.

For the past few years my laboratory has studied a group of inherited neurodegenerative diseases known as polyglutamine diseases. Eight polyglutamine diseases have already been identified, the most well known being Huntington disease. Polyglutamine diseases are so named because they are due to an abnormal protein that contains an enlarged, or expanded, polyglutamine stretch. We have discovered that expanded polyglutamine protein aggregates within neurons and causes the cells to undergo a stress response. In research funded by the Ellison Medical Foundation New Scholar award, my laboratory will identify the cellular players that mediate this stress response and determine whether their presence is good or bad for the neuron. Similar stress probably occurs in other neurodegenerative diseases, and perhaps even as part of normal aging. We are thus interested in applying our findings on polyglutamine disease to more common age-related degenerative diseases. Toward this goal, we recently developed cellular models of Parkinson disease that will allow us to define the broader role of the stress response in neurodegeneration. We hope that our research will identify components of the stress response which can then be modulated in ways to develop novel therapies for these incurable disorders.

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