Kino Y, Washizu C, Kurosawa M, Yamada M, Miyazaki H, Akagi T, Hashikawa T, Doi H, Takumi T, Hicks GG, Hattori N, Shimogori T, Nukina N. FUS/TLS deficiency causes behavioral and pathological abnormalities distinct from amyotrophic lateral sclerosis. Acta Neuropathol Commun. 2015 Apr 25;3:24. PubMed.
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Instiute of Psychiatry, King's College London
This paper is a really interesting read. Having been able to generate a line of FUS KO mice that live into adulthood, the authors offer some insight into the function of FUS through development and the lifespan of a mouse. It is interesting that an outbred background allows mice to survive, perhaps showing that FUS is less essential than people thought. In addition, the differences between this knockout and the changes seen when knockdown experiments are performed in vitro suggest that a compensatory mechanism exists for a complete lack of FUS.
The phenotype revealed in this knockout has some behavioral abnormalities that might be important for FTLD, though this was not conclusive. That there are no major neuronal changes despite the lack of FUS indicates that mutations in ALS-FUS cause disease by a “gain of function” mechanism. Given the difference in ALS-FUS and FLTD-FUS pathology, the lack of FUS mutations in the latter, and the changes seen in these mice, it is possible that the FTLD phenotype might be a result of a reduction in the amount of the WT FUS protein.
What it clearly shows is that very little is yet understood about the normal function of FUS within a neuron and that more work is needed to fully understand the protein’s role in cells, and therefore what its role is in neurodegenerative disease.
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