• Home
  • Search Results
  • EXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia.

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

Nature communications (2014-07-06)
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, Rita Horvath
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
L-Glutamine, meets USP testing specifications, suitable for cell culture, 99.0-101.0%, from non-animal source
Sigma-Aldrich
Anti-β-Actin antibody, Mouse monoclonal, clone AC-15, purified from hybridoma cell culture
Sigma-Aldrich
Osmium tetroxide, ReagentPlus®, 99.8%
Sigma-Aldrich
L-Glutamine, ReagentPlus®, ≥99% (HPLC)
SAFC
L-Glutamine
Sigma-Aldrich
Osmium tetroxide, Sealed ampule.
Sigma-Aldrich
Osmium tetroxide solution, suitable for electron microscopy, 4% in H2O
Sigma-Aldrich
Osmium tetroxide solution, 4 wt. % in H2O
Sigma-Aldrich
L-Glutamine, BioUltra, ≥99.5% (NT)
Sigma-Aldrich
L-Glutamine, γ-irradiated, BioXtra, suitable for cell culture
Sigma-Aldrich
Osmium tetroxide solution, 2.5 wt. % in tert-butanol
Sigma-Aldrich
Osmium tetroxide solution, suitable for electron microscopy, 2% in H2O
Supelco
L-Glutamine, Pharmaceutical Secondary Standard; Certified Reference Material
Supelco
L-Glutamine, certified reference material, TraceCERT®
Sigma-Aldrich
Osmium tetroxide, ACS reagent, ≥98.0%
Sigma-Aldrich
Os EnCat® 40, extent of labeling: 0.3 mmol/g Os loading
Sigma-Aldrich
L-Glutamine
Sigma-Aldrich
Anti-EXOSC8 (C-terminal) antibody produced in rabbit, ~1.0 mg/mL, affinity isolated antibody