Annexin A5 directly interacts with amyloidogenic proteins and reduces their toxicity.
Protein misfolding is a central mechanism for the development of neurodegenerative diseases and type 2 diabetes mellitus. The accumulation of misfolded alpha-synuclein protein inclusions in the Lewy bodies of Parkinson's disease is thought to play a key role in pathogenesis and disease progression. Similarly, the misfolding of the beta-cell hormone human islet amyloid polypeptide (h-IAPP) into toxic oligomers plays a central role in the induction of beta-cell apoptosis in the context of type 2 diabetes. In this study, we show that annexin A5 plays a role in interacting with and reducing the toxicity of the amyloidogenic proteins, h-IAPP and alpha-synuclein. We find that annexin A5 is coexpressed in human beta-cells and that exogenous annexin A5 reduces the level of h-IAPP-induced apoptosis in human islets by approximately 50% and in rodent beta-cells by approximately 90%. Experiments with transgenic expression of alpha-synuclein in Caenorhabditis elegans show that annexin A5 reduces alpha-synuclein inclusions in vivo. Using thioflavin T fluorescence, electron microscopy, and electron paramagnetic resonance, we provide evidence that substoichiometric amounts of annexin A5 inhibit h-IAPP and alpha-synuclein misfolding and fibril formation. We conclude that annexin A5 might act as a molecular safeguard against the formation of toxic amyloid aggregates.
Bedrood
Sahar
S
Department of Biochemistry and Molecular Biology, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
Jayasinghe
Sajith
S
Sieburth
Derek
D
Chen
Min
M
Erbel
Saskia
S
Butler
Peter C
PC
Langen
Ralf
R
Ritzel
Robert A
RA
D000682:Amyloid / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D030801:Animals, Genetically Modified; D017304:Annexin A5 / Q000378:metabolism*; D017209:Apoptosis; D017173:Caenorhabditis elegans; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D058228:Islet Amyloid Polypeptide; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D017510:Protein Folding; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
D000682:Amyloid; D017304:Annexin A5; D058228:Islet Amyloid Polypeptide; D051844:alpha-Synuclein