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Flinn L.J.,University of Sheffield | Keatinge M.,University of Sheffield | Bretaud S.,University of Sheffield | Mortiboys H.,University of Sheffield | And 18 more authors.
Annals of Neurology | Year: 2013

Objective Loss of function mutations in PINK1 typically lead to early onset Parkinson disease (PD). Zebrafish (Danio rerio) are emerging as a powerful new vertebrate model to study neurodegenerative diseases. We used a pink1 mutant (pink-/-) zebrafish line with a premature stop mutation (Y431*) in the PINK1 kinase domain to identify molecular mechanisms leading to mitochondrial dysfunction and loss of dopaminergic neurons in PINK1 deficiency. Methods The effect of PINK1 deficiency on the number of dopaminergic neurons, mitochondrial function, and morphology was assessed in both zebrafish embryos and adults. Genome-wide gene expression studies were undertaken to identify novel pathogenic mechanisms. Functional experiments were carried out to further investigate the effect of PINK1 deficiency on early neurodevelopmental mechanisms and microglial activation. Results PINK1 deficiency results in loss of dopaminergic neurons as well as early impairment of mitochondrial function and morphology in Danio rerio. Expression of TigarB, the zebrafish orthologue of the human, TP53-induced glycolysis and apoptosis regulator TIGAR, was markedly increased in pink-/- larvae. Antisense-mediated inactivation of TigarB gave rise to complete normalization of mitochondrial function, with resulting rescue of dopaminergic neurons in pink-/- larvae. There was also marked microglial activation in pink-/- larvae, but depletion of microglia failed to rescue the dopaminergic neuron loss, arguing against microglial activation being a key factor in the pathogenesis. Interpretation Pink1-/- zebrafish are the first vertebrate model of PINK1 deficiency with loss of dopaminergic neurons. Our study also identifies TIGAR as a promising novel target for disease-modifying therapy in PINK1-related PD. Ann Neurol 2013;74:837-847 © 2013 American Neurological Association.

Diaz-Munoz M.D.,Babraham Institute | Bell S.E.,Babraham Institute | Fairfax K.,Babraham Institute | Fairfax K.,Walter and Eliza Hall Institute of Medical Research | And 15 more authors.
Nature Immunology | Year: 2015

Post-transcriptional regulation of mRNA by the RNA-binding protein HuR (encoded by Elavl1) is required in B cells for the germinal center reaction and for the production of class-switched antibodies in response to thymus-independent antigens. Transcriptome-wide examination of RNA isoforms and their abundance and translation in HuR-deficient B cells, together with direct measurements of HuR-RNA interactions, revealed that HuR-dependent splicing of mRNA affected hundreds of transcripts, including that encoding dihydrolipoamide S-succinyltransferase (Dlst), a subunit of the 2-oxoglutarate dehydrogenase (α-KGDH) complex. In the absence of HuR, defective mitochondrial metabolism resulted in large amounts of reactive oxygen species and B cell death. Our study shows how post-transcriptional processes control the balance of energy metabolism required for the proliferation and differentiation of B cells. © 2015 Nature America, Inc. All rights reserved.

Stolz A.,Goethe University Frankfurt | Dikic I.,Goethe University Frankfurt | Dikic I.,Buchmann Institute for Molecular Life science
Molecular Cell | Year: 2014

By using quantitative proteomics, Ordureau etal. (2014) provide a comprehensive view on the regulatory steps by which PINK1-mediated phosphorylation of PARKIN and ubiquitin triggers the recruitment of the ubiquitin ligase PARKIN to damaged mitochondria. © 2014 Elsevier Inc.

Brieke C.,Goethe University Frankfurt | Rohrbach F.,University of Bonn | Gottschalk A.,Buchmann Institute for Molecular Life science | Mayer G.,University of Bonn | Heckel A.,Goethe University Frankfurt
Angewandte Chemie - International Edition | Year: 2012

Spatial and temporal control over chemical and biological processes plays a key role in life, where the whole is often much more than the sum of its parts. Quite trivially, the molecules of a cell do not form a living system if they are only arranged in a random fashion. If we want to understand these relationships and especially the problems arising from malfunction, tools are necessary that allow us to design sophisticated experiments that address these questions. Highly valuable in this respect are external triggers that enable us to precisely determine where, when, and to what extent a process is started or stopped. Light is an ideal external trigger: It is highly selective and if applied correctly also harmless. It can be generated and manipulated with well-established techniques, and many ways exist to apply light to living systems-from cells to higher organisms. This Review will focus on developments over the last six years and includes discussions on the underlying technologies as well as their applications. Spot on! Systems which can be regulated by using light as a trigger can be used for very sophisticated experiments in which aspects of space, time, or extent of activation are to be studied. Irreversible photocleavage, reversible photoswitching, and genetically expressible systems are the three possibilities for coupling the trigger to an effect. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Stolz A.,Goethe University Frankfurt | Ernst A.,Goethe University Frankfurt | Dikic I.,Goethe University Frankfurt | Dikic I.,Buchmann Institute for Molecular Life science
Nature Cell Biology | Year: 2014

Selective autophagy is a quality control pathway through which cellular components are sequestered into double-membrane vesicles and delivered to specific intracellular compartments. This process requires autophagy receptors that link cargo to growing autophagosomal membranes. Selective autophagy is also implicated in various membrane trafficking events. Here we discuss the current view on how cargo selection and transport are achieved during selective autophagy, and point out molecular mechanisms that are congruent between autophagy and vesicle trafficking pathways. © 2014 Macmillan Publishers Limited. All rights reserved.

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