This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A fundamental characteristic of neurodegenerative disorders is the accumulation and aggregation of ubiquitinated proteins in neuronal inclusions, such as neurofibrillary tangles in Alzheimer s disease (AD) and Lewy bodies in Parkinson s disease (PD). The identity of most ubiquitinated proteins that accumulate in neuronal inclusions and their role in the progression of neurodegeneration are unknown. The main objectives of this application are to characterize ubiquitinated proteins that accumulate and aggregate in neuronal cells under stress conditions associated with inflammation and to prevent protein aggregation to potentially hinder cell death. To accomplish our main objectives the following three specific aims are proposed: (1) Identify ubiquitinated proteins that accumulate and aggregate in prostaglandin J2 (PGJ2)-treated human SK-N-SH neuroblastoma cells using a proteomics approach. We propose that under stress conditions such as those induced by PGJ2, a neurotoxic product of inflammation, the sequestration of polyubiquitinated proteins into aggregates prevents their degradation and promotes cell death. We expect that characterization of polyubiquitinated proteins that accumulate under stress conditions will provide clues to aggregate biogenesis. (2) Establish that the polyubiquitinated proteins identified in specific aim 1 are detected in postmortem human brain tissue. We propose that polyubiquitinated proteins identified in specific aim 1, shown to accumulate and aggregate in SK-N-SH cells upon PGJ2-treatment, will also accumulate and aggregate in human brain under stress conditions associated with neurodegeneration. (3) Examine the potential of pharmacological strategies to prevent the aggregation of ubiquitinated proteins and loss of viability observed in stressed human SK-N-SH neuroblastoma cells upon PGJ2-treatment. We propose that prevention of the aggregation of polyubiquitinated proteins will promote their degradation with a concomitant survival of the neuronal cells. Overall, we expect that the characterization of polyubiquitinated proteins that accumulate and aggregate in stressed neuronal cells will provide insights into neuronal inclusion biogenesis and underscores the potential for the discovery of new targets for therapeutic intervention to prevent protein aggregation linked to neurodegeneration and the development of markers for individuals at risk for neurodegenerative disorders associated with the accumulation of ubiquitinated proteins in neuronal inclusions, such as AD and PD.
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