HIAPP and hproIAPP triggers elective autophagy and inhibit the neuro-­protective effect of autophagy

• Introduction: Amyloid formation is associated with cell death and islet amyloid is thought to participate in the 50-60% β-cell reduction detected in patients with type 2 diabetes. Islet amyloid polypeptide (IAPP) is the main amyloid protein in the islets of Langerhans. Initial IAPP-amyloid formation is intracellular and part of this amyloid constitutes of proIAPP. Material & methods: We have established a new model in Drosophila melanogaster where expression of hproIAPP and IAPP results in the formation of amyloid. With this model, we have investigated the effect of protein aggregation on pathways such as ER-stress, unfolded protein response (UPR), apoptosis and autophagy. Important steps in the different pathways were manipulated by RNAi-technique or over- expression of endogenous Drosophila proteins. Results: Expression of hproIAPP and hIAPP driven to the pdf-neurons led to cell death, but this was without activation of ER-stress, UPR or apoptosis. Aggregated hproIAPP and IAPP, labeled with antibodies against ubiquitin and p62 were accumulated intracellular, a finding that points to an involvement of autophagy. HproIAPP and hIAPP were shown to exert their toxic activity by an intracellular mechanism in contrary to Aβ42 and Aβ42 E22G that exhibit an extracellular toxic activity. Conclusion: Studies on toxicity suggest that hproIAPP and hIAPP aggregates can occupy the autophagy pathway and prevent maintenance of basal cellular homeostasis. Comparison of proIAPP/IAPP and Aβ42 toxicity shows that amyloid proteins of separate origin can exhibit different toxicity.

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MEDICINE

MEDICIN

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vet (subject category)

ovr (subject category)