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Role of polyphosphate in redox status during amyloidogenic processes using genetically encoded fluorescent sensors

Grant number: 16/20864-8
Support type:Scholarships abroad - Research
Effective date (Start): March 01, 2017
Effective date (End): September 30, 2017
Field of knowledge:Biological Sciences - Biochemistry - Metabolism and Bioenergetics
Principal researcher:Denise de Castro Fernandes
Grantee:Denise de Castro Fernandes
Host: Ursula H. Jakob
Home Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Research place: University of Michigan, United States  
Associated research grant:13/07937-8 - Redoxome - Redox Processes in Biomedicine, AP.CEPID

Abstract

The biopolymer polyphosphate (polyP), which is ubiquitously produced in every cell and organism studied so far, has recently been shown to stabilize proteins during oxidative stress conditions and to serve as a cytoprotective modifier of amyloidogenic processes. PolyP shows a remarkable efficacy in accelerating amyloid fibril formation. By serving as effective nucleation source for various different amyloid proteins, it accelerates fibril formation and prevents the accumulation of toxic oligomers. In vivo, the amyloid-stimulating and fibril-stabilizing effects of polyP were shown to reduce amyloid toxicity in differentiated neuroblastoma cells as well as C. elegans models for human folding diseases. Amyloid toxicity has been associated with oxidative stress conditions, by mechanisms involving the unfolded protein response activation in endoplasmic reticulum. Here we aim to establish Orp1-based genetically encoded fluorescent redox sensor proteins to monitor and potentially disrupt amyloid-induced peroxide production and test how polyP affects intracellular H2O2 production during amyloid aggregation in vivo. By using isolated neurons from mice that overexpress the redox sensors either in the cytosol or in mitochondria, we will provide a kinetic read-out as to when cells encounter oxidative stress upon incubation with freshly secreted amyloids or pre-formed amyloid fibrils, and test whether polyP's cytoprotective action might be in part to mitigating oxidative damage in neuronal cells.

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