Qiu H, Lee S, Shang Y, Wang WY, Au KF, Kamiya S, Barmada SJ, Finkbeiner S, Lui H, Carlton CE, Tang AA, Oldham MC, Wang H, Shorter J, Filiano AJ, Roberson ED, Tourtellotte WG, Chen B, Tsai LH, Huang EJ.
ALS-associated mutation FUS-R521C causes DNA damage and RNA splicing defects.
J Clin Invest. 2014 Mar 3;124(3):981-99. Epub 2014 Feb 10
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It is always encouraging when another model of ALS is published. The more models we have, the more we can find out and the faster we can get to therapies. This model specifically overexpresses a mutant form of FUS. The onset of disease occurs very early in these mice, which might relate directly to the overall levels of FUS expressed in these animals. Although the mutant form is expressed at a similar level to the endogenous one in these transgenics, the overall increase in expression is significantly higher compared to a non-transgenic. It has been shown in both FUS and TDP models of disease that the age of onset seems related to the level of overexpression rather than the mutation (both wild-type FUS and wild-type TDP overexpression mouse models show neurodegenerative-like phenotypes).
It is also interesting that in these animals there is no sign of downregulation of the endogenous protein, which might result from the mutation because FUS is known to self-regulate (by splicing its own mRNA, which leads it to be degraded) and does so in other models (Mitchell et al., 2013). What is not clear is whether this model can tell us anything about FTLD-FUS. It might be that FTLD-FUS is not caused primarily by a FUS deficit but by a disruption of pathways in which it is involved. Certainly there are other proteins, such as TAF15 and EWS and TNPO1, which are found in FTLD-FUS inclusions but are not found in ALS-FUS inclusions.
The authors report that the mutant and wild-type FUS form complexes. That agrees with a variety of papers that suggest that this is the case. It is perhaps surprising that they did not find an interaction between the WT protein and itself, as has been previously published. I think that the formation of these stable complexes is very interesting, as it fits with the hypothesis that the mutant protein can sequester the wild-type protein within cytoplasmic aggregates in ALS. Given that a single base pair change can lead to such a devastating disease, it is not surprising that it might have such an effect in cell and animal models.
In this case I suspect that the lack of accumulation of FUS in the cytoplasm has more to do with longevity, because the level of FUS seems fairly toxic to the mice and they only live a short while. I suspect that the expression is high in these animals and that a lower sustained expression of FUS would more likely result in aggregates. Previous models showed that increasing the overall expression level of WT FUS by 1.4- to 1.9-fold was sufficient to result in an aggressive, fatal phenotype. I feel that this model, like most models, tells us something about the mechanism of disease but does not fully recapitulate the disease. After all, we are comparing a disease that takes a few decades to manifest (even in the FUS families) to a very rapid onset in the models. I think that all overexpression models, regardless of whether they are WT or mutant forms of the protein, tell us that FUS, like TDP43, is a heavily regulated protein and that under- or overexpression of it results in cell death. This suggests that there are critical cell functions that are carried out by FUS for which any disruption results in problems for the cell.
I think that the RNA work that has been done in this paper and the neuronal changes seen here, linked with recent publications on both TDP and FUS in the nervous system, suggests that a disruption of RNA metabolism in the neurons leading to altered synaptic function and ultimately cell death is a likely disease mechanism.
Mitchell JC, McGoldrick P, Vance C, Hortobagyi T, Sreedharan J, Rogelj B, Tudor EL, Smith BN, Klasen C, Miller CC, Cooper JD, Greensmith L, Shaw CE.
Overexpression of human wild-type FUS causes progressive motor neuron degeneration in an age- and dose-dependent fashion.
Acta Neuropathol. 2012 Sep 9;