Pur-alpha functionally interacts with FUS carrying ALS-associated mutations.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder due to motor neuron loss. Fused in sarcoma (FUS) protein carrying ALS-associated mutations localizes to stress granules and causes their coalescence into larger aggregates. Here we show that Pur-alpha physically interacts with mutated FUS in an RNA-dependent manner. Pur-alpha colocalizes with FUS carrying mutations in stress granules of motoneuronal cells differentiated from induced pluripotent stem cells and that are derived from ALS patients. We observe that both Pur-alpha and mutated FUS upregulate phosphorylation of the translation initiation factor eukaryotic translation initiation factor 2 alpha and consistently inhibit global protein synthesis. In vivo expression of Pur-alpha in different Drosophila tissues significatively exacerbates the neurodegeneration caused by mutated FUS. Conversely, the downregulation of Pur-alpha in neurons expressing mutated FUS significatively improves fly climbing activity. All these findings suggest that Pur-alpha, through the control of mRNA translation, might be involved in the pathogenesis of ALS associated with the mutation of FUS, and that an alteration of protein synthesis may be directly implicated in the disease. Finally, in vivo RNAi-mediated ablation of Pur-alpha produced locomotion defects in Drosophila, indicating a pivotal role for this protein in the motoneuronal function.
IBPM, Istituto di Biologia e Patologia Molecolari, CNR, Rome, Italy.|University of Rome 'Sapienza', Department of Biology and Biotechnology, Rome, Italy.
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Di Salvio
IBPM, Istituto di Biologia e Patologia Molecolari, CNR, Rome, Italy.|University of Rome 'Sapienza', Department of Biology and Biotechnology, Rome, Italy.
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Piccinni
Laboratory of Neurochemistry, Fondazione Santa Lucia, IRCCS, Rome, Italy.
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Gerbino
IBPM, Istituto di Biologia e Patologia Molecolari, CNR, Rome, Italy.|University of Rome 'Sapienza', Department of Biology and Biotechnology, Rome, Italy.
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Mantoni
Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
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Camerini
Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.
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Lenzi
University of Rome 'Sapienza', Department of Biology and Biotechnology, Rome, Italy.
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Rosa
Department of Biology, University of Rome 'Tor Vergata', Rome, Italy.
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Chellini
Department of Biology, University of Rome 'Tor Vergata', Rome, Italy.
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Loreni
Laboratory of Neurochemistry, Fondazione Santa Lucia, IRCCS, Rome, Italy.|Department of Biology, University of Rome 'Tor Vergata', Rome, Italy.
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Carrì
University of Rome 'Sapienza', Department of Biology and Biotechnology, Rome, Italy.|Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.
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Bozzoni
Laboratory of Neurochemistry, Fondazione Santa Lucia, IRCCS, Rome, Italy.|IFT, Istituto di Farmacologia Traslazionale, CNR, Rome, Italy.
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Cozzolino
IBPM, Istituto di Biologia e Patologia Molecolari, CNR, Rome, Italy.|University of Rome 'Sapienza', Department of Biology and Biotechnology, Rome, Italy.
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Cestra
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004330:Drosophila / Q000235:genetics / Q000502:physiology; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D009046:Motor Neurons / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000235:genetics; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012270:Ribosomes / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D015852:Eukaryotic Initiation Factor-2; D009419:Nerve Tissue Proteins; C501130:PURA protein, human; C545199:Pur-alpha protein, Drosophila; C121485:Pura protein, mouse; D012333:RNA, Messenger; D034702:RNA-Binding Protein FUS; D014157:Transcription Factors