The Role of Proteolysis in Amyloidosis

Abstract

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, β-amyloid precursor protein, and α-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.

Selective protein aggregation confines and inhibits endotoxins in wounds: Linking host defense to amyloid formation

“… 35 , 36 , 37 , 38 Proteolysis is a hallmark of inflammation in wounds 39 , 40 and it is therefore worth noting that amyloid aggregates are often composed of proteolytic fragments, derived from the degradation of precursor proteins. These fragments display higher amyloidogenic tendency compared to their precursor proteins, 41 a finding that provides an additional link to the LPS-induced amyloid formation in the AWFs observed in this report. Interestingly, a persistent inflammatory milieu can exacerbate amyloidosis, leading to a vicious cycle of inflammation and disease progression.…”

Plasminogen degrades α-synuclein, Tau and TDP-43 and decreases dopaminergic neurodegeneration in mouse models of Parkinson’s disease

“…One of the typical pathological features of PD is the formation of misfolded protein aggregates (Lewy bodies) of α-synuclein (α-syn), which disrupt factors involved in proteostasis, such as chaperone proteins, the proteasome or autophagy, and eventually lead to the destruction of dopaminergic neurons 4 , 5 . Current drug development efforts aimed at decreasing α-syn aggregation have focused mainly on using different therapeutic antibodies, but these approaches have not resulted in convincing results of disease improvement 3 .…”

“…Current drug development efforts aimed at decreasing α-syn aggregation have focused mainly on using different therapeutic antibodies, but these approaches have not resulted in convincing results of disease improvement 3 . However, accumulating evidence has demonstrated that therapies that target α-syn clearance via proteolytic cleavage or autophagy may provide new therapeutic strategies for PD 4 .…”

β-Secretase-1: In Silico Drug Reposition for Alzheimer’s Disease

“…Its crystalline structure reveals that the proteolytic pocket is relatively large, being able to accommodate up to 11 amino acid residues [23,24]. Amyloid plaques, composed mainly of β-amyloid peptide, are progressively formed in the brain of Alzheimer's patients, and mutations in three genes cause the early onset of Familial Alzheimer's disease (FAD) by directly increasing the toxic peptide that promotes β-amyloid 42 [25][26][27]. β-Amyloid is the product of the catabolism of a large protein, the β-Amyloid Precursor Protein (APP) [27][28][29].…”