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Sci Rep. 2015 Dec 1;5:17332. doi: 10.1038/srep17332.

Neurodegenerative disease-associated mutants of a human mitochondrial aminoacyl-tRNA synthetase present individual molecular signatures.

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Architecture et Réactivité de l'ARN, CNRS, Université de Strasbourg, IBMC, 15 rue René Descartes, 67084 STRASBOURG Cedex, France.
Synchrotron SOLEIL, L'Orme des Merisiers Saint Aubin, 91410 Gif-sur-Yvette, France.
URBIA-Nantes, INRA Centre de Nantes, 60 rue de la Géraudière, 44316 Nantes, France.


Mutations in human mitochondrial aminoacyl-tRNA synthetases are associated with a variety of neurodegenerative disorders. The effects of these mutations on the structure and function of the enzymes remain to be established. Here, we investigate six mutants of the aspartyl-tRNA synthetase correlated with leukoencephalopathies. Our integrated strategy, combining an ensemble of biochemical and biophysical approaches, reveals that mutants are diversely affected with respect to their solubility in cellular extracts and stability in solution, but not in architecture. Mutations with mild effects on solubility occur in patients as allelic combinations whereas those with strong effects on solubility or on aminoacylation are necessarily associated with a partially functional allele. The fact that all mutations show individual molecular and cellular signatures and affect amino acids only conserved in mammals, points towards an alternative function besides aminoacylation.

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