Protein misfolding and aggregation cause a number of age-related neurodegenerative diseases, including Huntington’s, Parkinson’s, and most famously Alzheimer’s. Just yesterday, in fact, we discussed a paper about the interaction between genetic determinants of lifespan and a model of Alzheimer’s Aß aggregation in the worm C. elegans.

In each of these cases, the disease results from a mutation in the gene that encodes the particular misfolded or aggregated protein. Now, however, we have an example of a neurodegenerative syndrome that results from protein misfolding in general, which in turn results from a mutation in a tRNA synthetase.

Lee et al. break the news in the early online edition of a minor British journal:

Misfolded proteins are associated with several pathological conditions including neurodegeneration. Although some of these abnormally folded proteins result from mutations in genes encoding disease-associated proteins (for example, repeat-expansion diseases), more general mechanisms that lead to misfolded proteins in neurons remain largely unknown. Here we demonstrate that low levels of mischarged transfer RNAs (tRNAs) can lead to an intracellular accumulation of misfolded proteins in neurons. These accumulations are accompanied by upregulation of cytoplasmic protein chaperones and by induction of the unfolded protein response. We report that the mouse sticky mutation, which causes cerebellar Purkinje cell loss and ataxia, is a missense mutation in the editing domain of the alanyl-tRNA synthetase gene that compromises the proofreading activity of this enzyme during aminoacylation of tRNAs. These findings demonstrate that disruption of translational fidelity in terminally differentiated neurons leads to the accumulation of misfolded proteins and cell death, and provide a novel mechanism underlying neurodegeneration.

The sticky mouse was so named because of the appearance of its coat: the mutants exist in a sort of perpetual bad hair day. The wretched little beasts’ plight only worsens with time. By the time they’re a month old, their Purkinje cells have started dying off; in another month, they have the wobbling gait that is a hallmark of cerebellar dysfunction.

There’s no single protein at fault here (other than the faulty tRNA synthetase). Presumably all of the polypeptides in the cell are being synthesized with lower fidelity, causing the accumulation of all manner of misfolded proteins. (This reminds me that there’s a good recent review about the role ubiquitination-mediated protein degradation, specifically defects therein, might play in neurodegenerative diseases: see Ardley and Robinson).

Even though the mis-synthesis and misfolding is happening in all cells, the Purkinje cells suffer the most. This also happens in the single-wicked-mutant-protein diseases, even when the disease gene is widely expressed throughout the body: All cells have the potential to develop the problem, but the neurons of the brain (usually a subset of these) are hardest hit.

Why? Are neurons (or particular subsets of neurons) particularly bad at degrading misfolded proteins, or particularly sensitive to the ravages of accumulated trash? The authors favor some combination of the two, further suggesting that neurons might be extra-sensitive because they’re unable to dilute cellular detritus by dividing.

I don’t much care for the latter suggestion. There are a lot of non-dividing cells in the body at any given moment, and plenty of technically dividing cells whose rate of division isn’t high enough to consider mitosis an effective means of diluting endogenous toxic species, so it doesn’t work well as a model to explain neuronal specificity. Especially given the mechanics of this particular mutation, the model falls flat: before they divide, cells have to make enough protein to fill both daughter cells …and in sticky mice, every protein is at risk of being mis-synthesized, so it would seems hard to get out from in front of the bus by making more protein.

Regardless, for now, we have a new genetic mechanism for neurodegeneration.

And…someone, please, get that mouse some conditioner.