(mentions CMT) An assessment of mechanisms underlying peripheral axonal degenera

[Guest guest]

Mol Cell Neurosci. 2010 Nov 26.

An assessment of mechanisms underlying peripheral axonal degeneration caused by

aminoacyl-tRNA synthetase mutations.

Stum M, McLaughlin HM, Kleinbrink EL, Miers KE, Ackerman SL, Seburn KL,

Antonellis A, Burgess RW.

The Laboratory, Bar Harbor, ME 04609, USA.

Abstract

Mutations in glycyl-, tyrosyl-, and alanyl-tRNA synthetases (GARS, YARS and AARS

respectively) cause autosomal dominant Charcot-Marie-Tooth disease, and

mutations in Gars cause a similar peripheral neuropathy in mice. Aminoacyl-tRNA

synthetases (ARSs) charge amino acids onto their cognate tRNAs during

translation; however, the pathological mechanism(s) of ARS mutations remains

unclear. To address this, we tested possible mechanisms using mouse models.

First, amino acid mischarging was discounted by examining the recessive " sticky "

mutation in alanyl-tRNA synthetase (Aars(sti)), which causes cerebellar

neurodegeneration through a failure to efficiently correct mischarging of

tRNA(Ala). Aars(sti/sti) mice do not have peripheral neuropathy, and they share

no phenotypic features with the Gars mutant mice. Next, we determined that the

Wallerian degeneration slow (Wlds) mutation did not alter the Gars phenotype.

Therefore, no evidence for misfolding of GARS itself or other proteins was

found. Similarly, there were no indications of general insufficiencies in

protein synthesis caused by Gars mutations based on yeast complementation

assays. Mutant GARS localized differently than wild type GARS in transfected

cells, but a similar distribution was not observed in motor neurons derived from

wild type mouse ES cells, and there was no evidence for abnormal GARS

distribution in mouse tissue. Both GARS and YARS proteins were present in

sciatic axons and Schwann cells from Gars mutant and control mice, consistent

with a direct role for tRNA synthetases in peripheral nerves. Unless defects in

translation are in some way restricted to peripheral axons, as suggested by the

axonal localization of GARS and YARS, we conclude that mutations in tRNA

synthetases are not causing peripheral neuropathy through amino acid mischarging

or through a defect in their known function in translation.