Aging and the Tissue Response to Misfolded Proteins

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DESCRIPTION (provided by applicant): Disorders of protein conformation of wild type proteins increase in frequency with aging. Alzheimers Disease, type II diabetes and senile systemic amyloidosis are the result of tissue deposition of the wild type protein precursors A2, islet amyloid polypeptide and transthyretin, respectively. In the case of A2 and the islet amyloid polypeptide, aggregation and deposition take occur in proximity to the cells producing the precursor proteins. In senile systemic amyloidosis, transthyretin is synthesized in the liver but deposits in the heart, gut and carpal tunnel, never the liver. Biophysical analyses of the processes of aggregation and fibril formation in vitro show similar kinetics for all three proteins, although transthyretin aggregation differs from the others in that it cannot be seeded. We have produced a transgenic model of senile systemic amyloidosis that resembles human senile systemic amyloidosis in terms of its target tissues (heart, gut, kidneys, but not liver), age of onset (from over one year to 2.5 years, and tissue deposition (non-fibrillar and fibrillar). In our analysis of the tissues of these animals, we have found that animals with significant cardiac deposition have a significantly different transcription pattern in both liver and heart than age and gender matched transgenic animals that do not display significant cardiac transthyretin deposition. We have hypothesized that the transcriptional response of the liver to presumably misfolded transthyretin plays a role in tissue deposition at a distance, i.e. in the heart. If the response is not qualitatively or quantitatively sufficient, partially misfolded transthyretin is released from the hepatocyte into the circulation and is free to aggregate and deposit in the heart and kidneys. We will use genomic and proteomic analyses and genetic crosses to investigate the molecular events in the liver, the state of circulating transthyretin, transcription patterns in the target tissues in the transgenic animals and how these vary with aging, genetically induced reduced responsiveness to oxidant stress, genetically determined chaperone deficiency, and a genetic defect in the innate immune response. At the completion of these studies, we should have a more complete understanding of the way in which intact higher organisms respond to potentially pathogenic misfolded proteins and how these processes are affected in aging.