EXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia

Veronika Boczonadi, Juliane S. Müller, Angela Pyle, Jennifer Munkley, Talya Dor, Jade Quartararo, Ileana Ferrero, Veronika Karcagi, Michele Giunta, Tuomo Polvikoski, Daniel Birchall, Agota Princzinger, Yuval Cinnamon, Susanne Lützkendorf, Henriett Piko, Mojgan Reza, Laura Florez, Mauro Santibanez-Koref, Helen Griffin, Markus Schuelke, Orly Elpeleg, Luba Kalaydjieva, Hanns Lochmüller, David J. Elliott, Patrick F. Chinnery, Shimon Edvardson () and Rita Horvath ()
Additional contact information
Veronika Boczonadi: Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway
Juliane S. Müller: Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway
Angela Pyle: Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway
Jennifer Munkley: Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway
Talya Dor: Hadassah– Hebrew University Medical Center
Jade Quartararo: University of Parma, Parco Area delle Scienze 11A
Ileana Ferrero: University of Parma, Parco Area delle Scienze 11A
Veronika Karcagi: NIEH, Albert Florian ut 2-6, Budapest 1097, Hungary
Michele Giunta: Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway
Tuomo Polvikoski: Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality
Daniel Birchall: Regional Neurosciences Centre, Queen Victoria Road, Newcastle upon Tyne NE1 4PL, UK
Agota Princzinger: Josa Andras Hospital, Szent Istvan utca 6, Nyiregyhaza 4400, Hungary
Yuval Cinnamon: Hadassah– Hebrew University Medical Center
Susanne Lützkendorf: Charité-Universitätsmedizin, Charité-Platz 1, 10117 Berlin, Germany
Henriett Piko: NIEH, Albert Florian ut 2-6, Budapest 1097, Hungary
Mojgan Reza: Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway
Laura Florez: Western Australian Institute for Medical Research/Centre for Medical Research, The University of Western Australia, 35 Stirling Highway Crawley, Western Australia 6009 Perth, Australia
Mauro Santibanez-Koref: Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway
Helen Griffin: Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway
Markus Schuelke: Charité-Universitätsmedizin, Charité-Platz 1, 10117 Berlin, Germany
Orly Elpeleg: Hadassah– Hebrew University Medical Center
Luba Kalaydjieva: Western Australian Institute for Medical Research/Centre for Medical Research, The University of Western Australia, 35 Stirling Highway Crawley, Western Australia 6009 Perth, Australia
Hanns Lochmüller: Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway
David J. Elliott: Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway
Patrick F. Chinnery: Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway
Shimon Edvardson: Hadassah– Hebrew University Medical Center
Rita Horvath: Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: Abstract The exosome is a multi-protein complex, required for the degradation of AU-rich element (ARE) containing messenger RNAs (mRNAs). EXOSC8 is an essential protein of the exosome core, as its depletion causes a severe growth defect in yeast. Here we show that homozygous missense mutations in EXOSC8 cause progressive and lethal neurological disease in 22 infants from three independent pedigrees. Affected individuals have cerebellar and corpus callosum hypoplasia, abnormal myelination of the central nervous system or spinal motor neuron disease. Experimental downregulation of EXOSC8 in human oligodendroglia cells and in zebrafish induce a specific increase in ARE mRNAs encoding myelin proteins, showing that the imbalanced supply of myelin proteins causes the disruption of myelin, and explaining the clinical presentation. These findings show the central role of the exosomal pathway in neurodegenerative disease.

Date: 2014
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DOI: 10.1038/ncomms5287

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