EXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia
Authors: Hanns Lochm√ºller
Henriett Piko
Shimon Edvardson
Markus Schuelke
Talya Dor
Mojgan Reza
Juliane S M√ºller
Helen Griffin
Jennifer Munkley
Yuval Cinnamon
Angela Pyle
Tuomo Polvikoski
Rita Horvath
Agota Princzinger
Luba Kalaydjieva
Mauro Santibanez-Koref
Daniel Birchall
Susanne L√ºtzkendorf
Laura Florez
Veronika Karcagi
Patrick F Chinnery
Veronika Boczonadi
Ileana Ferrero
Jade Quartararo
Michele Giunta
Orly Elpeleg
David J Elliott
Journal: Nature Communications (2014)
Discipline: Multidisciplinary
Keywords: exosome; EXOSC8; neurological disease; myelin proteins; ARE mRNAs
Affiliations: 1] Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK [2]., The Monique and Jacques Roboh Department of Genetic Research, Hadassah- Hebrew University Medical Center, Jerusalem 91120, Israel., Department of Life Sciences, University of Parma, Parco Area delle Scienze 11A, Parma 43124, Italy., Department of Molecular Genetics and Diagnostics, NIEH, Albert Florian ut 2-6, Budapest 1097, Hungary., Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK., Department of Pathology, Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK., Neuroradiology Department, Regional Neurosciences Centre, Queen Victoria Road, Newcastle upon Tyne NE1 4PL, UK., Department of Paediatrics, Josa Andras Hospital, Szent Istvan utca 6, Nyiregyhaza 4400, Hungary., 1] The Monique and Jacques Roboh Department of Genetic Research, Hadassah- Hebrew University Medical Center, Jerusalem 91120, Israel [2] Department of Poultry and Aquaculture Sciences, Institute of Animal Science, Agricultural Research Organization, The Volcani Center, P.O.Box 6, Bet Dagan 50250, Israel., Department of Neuropediatrics and NeuroCure Clinical Research Center, Charit√©-Universit√§tsmedizin, Charit√©-Platz 1, 10117 Berlin, Germany., Western Australian Institute for Medical Research/Centre for Medical Research, The University of Western Australia, 35 Stirling Highway Crawley, Western Australia 6009 Perth, Australia.

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. 

Retracted: No

PubPeer comments:
 Fig.7 a Plots 2 and 4 look remarkably similar to each other (mbp2 AU rich and PMP22 non-au rich) . Is it a mistake coming from the authors?  , 
 #1 We thank for this comment. We double checked our original Figure and it seems that during the publishing process image mbp2 was duplicated as pmp22 image. We have the correct Figure attached. I am very sorry for this mistake. Rita Horvath ,