Transthyretin (TTR) is a 55 kDa tetrameric protein that is folded in the endoplasmic reticulum and subsequently secreted into the blood, mainly by hepatocytes comprising the liver. Rate-limiting TTR tetramer dissociation and subsequent monomer misfolding leads to TTR aggregation�which is genetically and pharmacologically strongly linked to a variety of degenerative diseases, including polyneuropathies and cardiomyopathies. We will report a comprehensive biological and biochemical data package demonstrating that the composition of the cellular protein homeostasis network effects the stability of the TTR tetramer secreted, possibly explaining why only 10-15% of elderly males exhibit WT TTR dissociation and misfolding and thus develop senile systemic amyloidosis. Data supporting the hypothesis that mutant TTR tetramer stability is also influenced by its cellular environment during biogenesis will be presented. The cellular influence on the quality of the TTR tetramer secreted could also explain the incomplete penetrance of the familial TTR amyloidoses and may be the origins of the profound influence of genetic background on the age of onset of the TTR amyloidoses.

Cellular protein homeostasis network strongly influences the stability of secreted tetrameric transthyretin

248th National Meeting (2014)

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