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bioRxiv · 10.1101/046516

MicroRNA miR-29 controls a compensatory response to limit neuronal iron accumulation during adult life and aging

Roberto Ripa·Luca Dolfi·Marco Terrigno·Luca Pandolfini·Valeria Arcucci·Marco Groth·Eva Terzibasi Tozzini·Mario Baumgart·Alessandro Cellerino
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Abstract

Iron is an essential metal cofactor for enzymes involved in many cellular functions such as energy generation and cell proliferation. However, excessive iron concentration leads to increased oxidative stress and toxicity. As such, iron homeostasis is strictly controlled by two RNA binding proteins known as Iron Regulatory Proteins (IRPs) that regulate at post-transcriptional level the expression of iron management genes. Despite this fine regulation, impairment of iron homeostasis occurs during aging: iron progressively accumulates in several organs and in turn, it exacerbates cellular vulnerability and tissue decay. Moreover, excessive iron accumulation within the CNS is observed in many neurodegenerative diseases. We investigated the age-dependent changes of iron homeostasis using the short lived fish Nothobranchius furzeri. Here, we show that i) both iron content and expression of microRNA family miR-29 increase during adult life and aging in the N. furzeri brain; ii) iron up-regulates miR-29 expression in fish brain and murine neurons, while in turn miR-29 targets the 3'-UTR of IREB2 mRNA, reducing iron intake; iii) Transgenic fish with knock-down of miR-29 show significant adult-onset up-regulation of IRP2 and its target TFR1 in neurons and display enhanced age-dependent accumulation of brain iron; iv) miR-29 triggers a global gene expression response that partially overlaps with that induced by aging.\n\nOur studies indicate that miR-29 modulates intracellular iron homeostasis and is up-regulated as an adaptive response to limit excessive iron accumulation and prevent early-onset aging processes.

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Roberto Ripa, Luca Dolfi, Marco Terrigno, Luca Pandolfini, Valeria Arcucci, Marco Groth, Eva Terzibasi Tozzini, Mario Baumgart, Alessandro Cellerino. 2016-03-31. MicroRNA miR-29 controls a compensatory response to limit neuronal iron accumulation during adult life and aging. https://doi.org/10.1101/046516

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