A sticky subject

The accumulation of misfolded proteins in neurons is linked to pathogenesis in many neurodegenerative diseases, yet research directed at identifying mutations in disease-specific proteins that might cause such a build-up has been successful in only a few cases. Findings published in Nature now reveal a more general mechanism by which errors in the translation of the genetic code might lead to aberrant protein synthesis, misfolding and, eventually, cell death.

The new insights arose from analysis of a mutant mouse strain, which earned the name sticky (Sti) because of its dishevelled fur. Sti mice suffer from slow progressive degeneration of cerebellar Purkinje cells, leading to motor defects reminiscent of many neurodegenerative conditions. Ackerman and colleagues therefore set out to determine the genetic defect underlying this neurodegeneration.

The authors pinned down the mutation to the alanyl-tRNA synthetase (Aars) gene. AARS recognizes and links, by aminoacylation, the amino acid alanine to appropriate tRNA (tRNA^Ala) molecules and is crucial for the translation of mRNA transcripts into accurate peptide sequences. The mutation affects the editing domain of AARS, which deacylates tRNA^Alamolecules that are mistakenly bound to similarly sized but inappropriate amino acids, such as serine. As would be predicted, the mutation reduced the ability of the enzyme to deacylate serine–tRNA^Ala molecules, whereas the capacity to recognize alanine and catalyse appropriate aminoacylation reactions was unaffected.

To investigate the functional consequences of this reduced editing capacity the researchers examined the effects of high serine concentrations on cultured fibroblasts. Cell viability was reduced in mutant fibroblasts, accompanied by the intracellular accumulation of polyubiquitylated proteins indicative of protein misfolding.

In vivo, protein aggregates were observed in the Purkinje cells of Sti mice. Positive staining of Purkinje cells for ubiquitin and molecular chaperones, which are involved in the degradation of misfolded proteins, together with the presence of autophagosomes suggested that the cells were attempting to clear the aberrant proteins. An upregulation of molecules associated with endoplasmic reticulum stress provided a clue as to how the misfolded proteins might affect cell viability.

Given the ubiquitous nature of AARS, the restriction of neurodegeneration to cerebellar Purkinje cells seems counterintuitive. Potential explanations proposed by the authors include the possibility that Purkinje cells possess a reduced capacity to degrade such proteins or that other cell types make greater use of compensatory editing enzymes.

This study highlights the importance of editing during protein translation, showing that loss of this function can lead to the synthesis of misfolded proteins. As such defects might arise spontaneously or through inherited mutations, this mechanism might contribute to numerous neurodegenerative conditions. Moreover, therapeutics that boost endogenous editing activity might slow the progress of neurodegeneration.