CMT 2D: GARS axonopathy: not every neuron's cup of tRNA

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GARS axonopathy: not every neuron's cup of tRNA

Motley WW, Talbot K, Fischbeck KH.

Neurogenetics Branch, National Institute of Neurological Disorders and Stroke

(NINDS), National Institutes of Health (NIH), 35 Convent Drive, Bethesda, MD

20892-3705, USA; MRC Functional Genomics Unit, University of Oxford, Oxford, UK.

Charcot-Marie-Tooth disease type 2D, a hereditary axonal neuropathy, is caused

by mutations in glycyl-tRNA synthetase (GARS). The mutations are distributed

throughout the protein in multiple functional domains.

In biochemical and cell culture experiments, some mutant forms of GARS have been

indistinguishable from wild-type protein, suggesting that these in vitro tests

might not adequately assess the aberrant activity responsible for axonal

degeneration.

Recently, mouse and fly models have offered new insights into the disease

mechanism. There are still gaps in our understanding of how mutations in a

ubiquitously expressed component of the translation machinery result in axonal

neuropathy. Here, we review recent reports, weigh the evidence for and against

possible mechanisms and suggest areas of focus for future work.