The familial amyloidoses, on which the researchers focused their study, are caused by various mutations to a human protein called transthyretin (TTR). These mutations render transthyretin unstable and predisposed to misfolding from a normal, safe structure into dangerous, sticky ones that glom together and form microscopic fibrils, which then cluster to form larger amyloid plaques that deposit in peripheral nerves, organs, and sometimes in the central nervous system.
Strangely, some TTR mutations cause the fibrils to target the heart, others cause the fibrils to form in the peripheral nervous system, and still others cause the fibrils to form in the gut or in the brain. In the latest issue of the journal Cell, the Scripps Research team is describing the chemical and biological basis for this tissue selectivity.
It is not only, say the scientists, that certain tissues like the brain are more susceptible to the amyloid plaques because they are specifically targeted by misfolded TTR proteins, but rather because cells that secrete proteins into these tissues are the ones that secrete the bad proteins most efficiently.
"Most of the destabilized TTR variants tend to be secreted within susceptible tissues just as efficiently as normal TTR proteins, even though they are substantially destabilized," says Scripps Research Professor Jeffery W. Kelly, Ph.D., who led the research with Scripps Research Professor William E. Balch, Ph.D. Kelly is the Lita Annenberg Hazen Professor of Chemistry, a member of The Skaggs Institute for Chemical Biology, and Vice President of Academic Affairs at The Scripps Research Institute.