Cytotoxic Effects of Transthyretin Aggregates in an Epidermoid Cell Line

Abstract

Objective: Skin amyloid deposits can occur as part of systemic amyloidoses including those involving misfolded- aggregated transthyretins (agTTR). Pathological effects of agTTR on the skin are not well understood. The main objective of the current study was to examine the toxicity of agTTR upon a human keratinocyte cell line. Methods: Cells were analyzed for indicators of oxidative stress after treatment with normal soluble TTR or the same pre-aggregation concentration of agTTR. Hydrogen peroxide production was analyzed as an indicator for the involvement of reactive oxygen species. Results: Treatment of cells with agTTR significantly increased hydrogen peroxide production (p < 0.05 vs. controls). Glutathione (GSH) and catalase were analyzed as indicators of endogenous cellular antioxidant activity. Treatment of cells with agTTR resulted in significant decreases in both catalase activity and GSH levels (p < 0.05 vs. controls). Conclusion: agTTR disrupts redox balance and induces oxidative stress in these epidermoid cells.

Transthyretin Amyloid Cardiomyopathy: Impact of Transthyretin Amyloid Deposition in Myocardium on Cardiac Morphology and Function

“…TTR non-fibrillar aggregates induce a cytotoxic response that involves mitochondrial dysfunction, endoplasmic reticulum stress, and dysregulation of the Ca 2+ balance. Consequently, these cytotoxic responses may result in ROS accumulation and inflammation progression [ 17 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ].…”

Transthyretin: From Structural Stability to Osteoarticular and Cardiovascular Diseases

“…In contrast to the anti-oxidant properties of TTR, the aggregated TTR forms induce oxidative stress [ 83 , 84 , 85 , 86 ]. The DJ-1 protease is an important regulator of hypoxia-induced response [ 87 ].…”

“…In turn, TTR amyloid induces a cytotoxic response that involves ER stress, dysregulation of Ca 2+ balance, induction of UPR, upregulation of MMPs, apoptosis, and binding of membrane lipids [ 85 , 90 , 91 , 100 , 206 ]. Consequently, TTR amyloid contributes to oxidative stress and progression of inflammation [ 86 , 89 , 207 , 208 ]. In the plasma of FAP patients, the levels of cytokines (such as TNF-α, IL-1β, IL-8, IL-33, IFN-β, IL-10, and IL-12) are altered compared to those in healthy individuals [ 208 ].…”

Antioxidant Quercetin 3-O-Glycosylated Plant Flavonols Contribute to Transthyretin Stabilization

“…Deposition of aggregated forms of TTR is responsible of several side effects such as the dysregulation of physiological metals and, consequently, the production of reactive oxygen species (ROS) [23][24][25]. The relationship between TTR and ROS is not completely understood; however, several studies report that the free thiol of Cys10 is sensitive to oxidation, playing an important role in maintaining the stability of the tetramer [26].…”