The receptor for advanced glycation endproducts is a mediator of toxicity by IAPP and other proteotoxic aggregates: Establishing and exploiting common ground for novel amyloidosis therapies

Abstract

Proteotoxicity plays a key role in many devastating human disorders, including Alzheimer's, Huntington's and Parkinson's diseases; type 2 diabetes; systemic amyloidosis; and cardiac dysfunction, to name a few. The cellular mechanisms of proteotoxicity in these disorders have been the focus of considerable research, but their role in prevalent and morbid disorders, such as diabetes, is less appreciated. There is a large body of literature on the impact of glucotoxicity and lipotoxicity on insulin-producing pancreatic β-cells, and there is increasing recognition that proteotoxicty plays a key role. Pancreatic islet amyloidosis by the hormone IAPP, the production of advanced glycation endproducts (AGE), and insulin misprocessing into cytotoxic aggregates are all sources of β-cell proteotoxicity in diabetes. AGE, produced by the reaction of reducing sugars with proteins and lipids are ligands for the receptor for AGE (RAGE), as are the toxic pre-fibrillar aggregates of IAPP produced during amyloid formation. The mechanisms of amyloid formation by IAPP in vivo or in vitro are not well understood, and the cellular mechanisms of IAPP-induced β-cell death are not fully defined. Here, we review recent findings that illuminate the factors and mechanisms involved in β-cell proteotoxicity in diabetes. Together, these new insights have far-reaching implications for the establishment of unifying mechanisms by which pathological amyloidoses imbue their injurious effects in vivo.

Structural Features and Toxicity of α-Synuclein Oligomers Grown in the Presence of DOPAC

“…Amyloid binding to the membrane results in membrane functional and/or structural perturbation, with derangement of cell signaling [50][51][52] and alterations of free Ca 2+ and ROS levels [53,54]. Other effects, such as the interaction with membrane receptors [54][55][56][57] and the interference with signaling pathways have also been reported [56,58]. Syn accumulation has been shown to trigger neurotoxicity through aggregation-dependent mechanisms also in Gaucher disease, a severe neurological lysosomal storage disease, a group of metabolic diseases caused by lysosomal dysfunction [59][60][61][62].…”

Amyloid Proteins and Peripheral Neuropathy

“…Early in FAP development, non-fibrillar TTR aggregates are detected in nerve biopsies that are associated with signs of inflammation, e.g., increased expression of the proinflammatory cytokines TNF and IL-1β and iNOS in nerves [ 90 ]. Toxic protein aggregates cause inflammation through activating the receptor for advanced glycation end products (RAGE) and Toll-like receptors (TLR) [ 230 , 231 ], which activate the transcription factor NFκB, resulting in proinflammatory cytokine gene expression [ 232 , 233 ]. For example, in vitro, TTR binds RAGE and activates NFκB in transfected PC-12 cells [ 234 ].…”

Contribution of Oxidative Stress and Impaired Biogenesis of Pancreatic β-Cells to Type 2 Diabetes

“…Specifically, one polypeptide termed amylin is affected this way in islets in type 2 diabetes. The resulting antiparallel crossed β-pleated sheet structure amyloid is then sensitive to free radical polymerization and promotes significant β-cell cytotoxicity (1, 205, 298).…”