Does protein aggregation drive postmitotic tissue degeneration?

Abstract

Pharmacological evidence, from clinical trials where patients with systemic amyloid diseases are treated with disease-modifying therapies, supports the notion that protein aggregation drives tissue degeneration in these disorders. The protein aggregate structures driving tissue pathology and the commonalities in etiology between these diseases and Alzheimer's disease are under investigation.

Fig. 1.. Protein aggregation and mechanisms of toxicity.

Intrinsically disordered and folded proteins undergo a conformational change that renders them aggregation competent (top). Aggregation-prone proteins form a spectrum of aggregates including amyloid fibrils (middle) that are postulated to contribute to tissue degeneration. These aggregates may be in circulation, deposited in the extracellular spaces and plasma membranes of postmitotic tissues and may enter cells through endocytic pathways. The non-native protein structures responsible for pathogenic processes leading to tissue degeneration remain unclear, but a variety of mechanisms are likely to be involved (bottom). These mechanisms include deficits in protein trafficking and transport, mitochondrial dysfunction, and activation of inflammation. The amyloid hypothesis of AD posits that the process of Aβ aggregation in the brain leads to neurodegeneration and dementia. Clinical testing of disease-modifying therapies in patients with TTR amyloidosis, light chain amyloidosis, and serum amyloid A amyloidosis provides an opportunity to investigate the amyloid hypothesis in these three amyloidoses. Clinical data suggest that protein aggregation drives tissue degeneration in these three systemic amyloid diseases, but the data from AD clinical trials remain inconclusive regarding support for the amyloid hypothesis of AD.