The Role of Proteolysis in Amyloidosis

Amyloidoses are a group of diseases associated with deposits of amyloid fibrils in different tissues. So far, 36 different types of amyloidosis are known, each due to the misfolding and accumulation of a specific protein. Amyloid deposits can be found in several organs, including the heart, brain, kidneys, and spleen, and can affect single or multiple organs. Generally, amyloid-forming proteins become prone to aggregate due to genetic mutations, acquired environmental factors, excessive concentration, or post-translational modifications. Interestingly, amyloid aggregates are often composed of proteolytic fragments, derived from the degradation of precursor proteins by yet unidentified proteases, which display higher amyloidogenic tendency compared to precursor proteins, thus representing an important mechanism in the onset of amyloid-based diseases. In the present review, we summarize the current knowledge on the proteolytic susceptibility of three of the main human amyloidogenic proteins, i.e., transthyretin, beta-amyloid precursor protein, and alpha-synuclein, in the onset of amyloidosis. We also highlight the role that proteolytic enzymes can play in the crosstalk between intestinal inflammation and amyloid-based diseases.

Automated summary

Amyloidoses are diseases caused by the accumulation of misfolded proteins known as amyloid fibrils in various organs. There are currently 36 different types of amyloidosis, each associated with the misfolding of a specific protein. The aggregation of amyloid-forming proteins can be caused by genetic mutations, environmental factors, excessive concentration, or post-translational modifications. This review focuses on the proteolytic susceptibility of three main amyloidogenic proteins and their connection to intestinal inflammation.