The biological and chemical basis for tissue-selective amyloid disease

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Background:

• Extracellular amyloid diseases' onset and progression factors are poorly understood.
• Endoplasmic reticulum (ER) machinery's role in targeting misfolded proteins for degradation is crucial.
• Secreted protein variants often exhibit enhanced aggregation tendencies.

Purpose of the Study:

• To investigate the factors controlling the secretion and degradation of transthyretin (TTR) variants.
• To understand the role of protein folding energetics in ER-associated degradation (ERAD) versus ER-assisted folding and export (ERAF).
• To elucidate the mechanisms behind tissue-selective amyloidosis.

Main Methods:

• Utilized mammalian cell culture systems to study TTR variant secretion.
• Analyzed protein folding energetics and stability of TTR variants.
• Investigated the interplay between ERAD and ERAF pathways.

Main Results:

• Mammalian cells secrete various TTR disease-associated variants with wild-type efficiency, despite compromised folding.
• Only highly destabilized TTR variants undergo ERAD, and this is tissue-specific.
• ER-assisted folding (ERAF), based on global protein energetics, governs protein export efficiency.

Conclusions:

• ERAD and ERAF, influenced by protein energetics and cellular factors, determine a protein's secretory fate.
• Tissue-specific differences in ERAF and ERAD contribute to the varying susceptibility to amyloidosis.
• Protein folding energetics, rather than a strict stability threshold, dictates ER export versus degradation.