An assessment of mechanisms underlying peripheral axonal degeneration caused by aminoacyl-tRNA synthetase mutations.

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.

Pathologic assessment of cerebellar atrophy following acute lithium intoxication.

Lithium carbonate is a widely used pharmacologic agent for acute bipolar disorder, long term prophylaxis of mania in a bipolar patient, and prevention of "manic overshoot" with an antidepressant in acute depression in a bipolar patient. Although clinical neurological associations with lithium overdose have been-established, there has been a dearth of reports of pathologic changes related to lithium toxicity. We report a case of a 52-year-old Black female with bipolar disorder who had been treated with lithium for over 5 years and who expired 24 days after presenting in a stuporous state with an elevated lithium level of 3.2 mEq/l. Postmortem neuropathologic examination revealed severe cerebellar atrophy of the internal granule and Purkinje cell layers with attendant Bergmann gliosis presumably resulting from chronic lithium use and toxicity. There was also Alzheimer type II cell change in the thalamus and lentiform nuclei possibly due to terminal uremia. In summary, this is a unique case which appears to illustrate cerebellar atrophic changes related to lithium therapy and acute lithium intoxication.

Mitochondrial changes in rat Purkinje cells after prolonged alcohol consumption. A morphologic assessment.

The effects of chronic alcohol consumption on the mitochondria of Purkinje cells from the adult rat cerebellar cortex was examined with ultrastructural morphometric methods. Groups of controls and animals which were fed alcohol for periods of 1, 3, 6, 12 and 18 months were studied. Enlargement of the mitochondrial profiles was noted after one month of alcohol intake. The enlargement was significantly different in animals fed alcohol for 3 and 6 months when compared to controls. This alteration was no longer evident in the 12 and 18 months alcohol-fed groups, although by this time large numbers of ring-shaped mitochondria, occasionally filled by dense deposits, appeared in the Purkinje cell somas and in their apical dendrites. All these changes appeared regardless of variations in the number of these organelles per unit surface of cell cytoplasm. This data lends evidence that long-term exposure to ethanol, as has been shown to happen in the liver, induces marked structural mitochondrial alterations in the central nervous system.