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Triggering of intracellular aggregation and cytotoxicity by immature forms of human Islet Amyloid Polypeptide
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Orientador(es)
Resumo(s)
Diabetes is a chronic metabolic disease with increasing numbers worldwide. Pancreatic
deposits of human Islet Amyloid Polypeptide (hIAPP) represent the major histopathological hallmark of
type 2 diabetes. IAPP is a hormone produced by β-cells, which is released upon glucose stimulation
concomitantly with insulin, acting on gastric emptying and glycemic control. It is synthesized as
preproIAPP (ppIAPP) hormone that is first processed to proIAPP (pIAPP) and finally to its mature form
(matIAPP). Impairment in IAPP processing seems to be associated with the accumulation of immature
IAPP forms, leading to the formation of toxic intracellular aggregates, which have been associated with
β-cell dysfunction and loss. Currently, IAPP proteotoxicity is not fully understood. The main goals of this
study were to investigate the pathological role of immature IAPP forms involved in intracellular
aggregation and to test the potential protective activity of tauroursodeoxycholic acid (TUDCA) towards
IAPP-induced cytotoxicity. To this end, Saccharomyces cerevisiae models recapitulating IAPP
intracellular aggregation were characterized. Expression of human ppIAPP, pIAPP, and matIAPP
fusions with green fluorescent protein (GFP) induced toxicity in yeast cells, with ppIAPP exerting the
most deleterious effect on yeast growth and cell viability. Moreover, the expression of all IAPP
constructs led to the formation of intracellular aggregates with different biochemical features. The first
steps on generating a pancreatic β-cell line (INS-1) stably expressing hIAPP were also conducted.
Overall, the data obtained suggest that the accumulation of immature hIAPP forms triggers the
formation of highly cytotoxic intracellular aggregates. Although TUDCA has been shown to overcome
proteotoxicity induced by amyloid proteins, neither TUDCA nor ursodeoxycholic acid (UDCA) were able
to protect yeast cells against the toxic effects of hIAPP aggregates. These novel yeast models represent
powerful tools for future research focused on IAPP-induced toxicity and to screen for compounds
mitigating the deleterious effects caused by IAPP aggregation.
Descrição
Palavras-chave
Amylin Diabetes IAPP Protein aggregation Saccharomyces cerevisiae TUDCA