Grant: Operating Grant

We examine how long-lived cells maintain their function for the lifetime of the organism. While relevant to many cell types, this question is particularly relevant in the nervous system. Neurons must function through life to maintain normal brain function and are mostly irreplaceable. The function of any neuron depends upon its unique repertoire of effector genes that mediates the functions of the neuron. The expression of any neuron's effector genes is initiated during development by transcription factors (TFs) expressed in that neuron. The conventional paradigm assumes that the stability of mature neurons is a default state that is disrupted only by trauma or overt pathology. However, our recent work shows that the TFs initiated during development must persist to maintain effector gene expression throughout life. Thus, a neuron's gene expression profile is not locked in to a static state, but is instructively maintained by an active, dynamic process of persistent gene activation. We propose that these dynamic, instructive processes that are required to maintain mature neuronal function represents an Achilles heal that makes mature neurons vulnerable to degeneration. Genetic evidence supporting our proposal is provided by findings that degradation of TF function in aging neurons can lead to age-related neurodegeneration, such as Parkinson's disease. In this proposal we examine the mechanisms that actively maintain TF networks in mature neurons. These studies will be the first to define the mechanisms that maintain the integrity of transcriptional networks in mature neurons and will be the first to test a novel hypothesis for why the aging brain becomes vulnerable to degeneration. By defining these dynamic instructive mechanisms, we will provide a novel paradigm for identifying the causes, and providing therapeutic avenues, for age related degeneration of the nervous system.