A homozygous ATAD1 mutation impairs postsynaptic AMPA receptor trafficking and causes a lethal encephalopathy
| Autor: | Mark I. Rees, Juliette Piard, Frederike L. Harms, Henry Houlden, George K.E. Umanah, Malik Alawi, Seo-Kyung Chung, Ted M. Dawson, Valina L. Dawson, Melissa Chang, Lionel Van Maldergem, Alain Verloes, Rong Chen, Leire Abalde-Atristain, Vincenzo Salpietro, Kerstin Kutsche, Daniel Amram |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Models Molecular Male Mutant DNA Mutational Analysis Messenger Mitochondrion Encephalopathy medicine.disease_cause 0302 clinical medicine Models Receptors AMPA ATAD1 Internalization Receptor media_common Adenosine Triphosphatases Neurons Mutation Brain Diseases Chemistry Homozygote Magnetic Resonance Imaging Cell biology Mitochondria Protein Transport Female AMPA receptor trafficking ATPases Associated with Diverse Cellular Activities Carrier Proteins Family Health Gene Expression Regulation Humans Infant Multiprotein Complexes Nerve Tissue Proteins Oxygen Consumption RNA Messenger Receptors AMPA media_common.quotation_subject Protein subunit AMPA receptor Frameshift mutation 03 medical and health sciences Report medicine Molecular 030104 developmental biology RNA Neurology (clinical) 030217 neurology & neurosurgery |
| Popis: | Members of the AAA+ superfamily of ATPases are involved in the unfolding of proteins and disassembly of protein complexes and aggregates. ATAD1 encoding the ATPase family, AAA+ domain containing 1-protein Thorase plays an important role in the function and integrity of mitochondria and peroxisomes. Postsynaptically, Thorase controls the internalization of excitatory, glutamatergic AMPA receptors by disassembling complexes between the AMPA receptor-binding protein, GRIP1, and the AMPA receptor subunit GluA2. Using whole-exome sequencing, we identified a homozygous frameshift mutation in the last exon of ATAD1 [c.1070_1071delAT; p.(His357Argfs*15)] in three siblings who presented with a severe, lethal encephalopathy associated with stiffness and arthrogryposis. Biochemical and cellular analyses show that the C-terminal end of Thorase mutant gained a novel function that strongly impacts its oligomeric state, reduces stability or expression of a set of Golgi, peroxisomal and mitochondrial proteins and affects disassembly of GluA2 and Thorase oligomer complexes. Atad1(−/−) neurons expressing Thorase mutant(His357Argfs*15) display reduced amount of GluA2 at the cell surface suggesting that the Thorase mutant may inhibit the recycling back and/or reinsertion of AMPA receptors to the plasma membrane. Taken together, our molecular and functional analyses identify an activating ATAD1 mutation as a new cause of severe encephalopathy and congenital stiffness. |
| Databáze: | OpenAIRE |
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