Fujioka Y, Ishigaki S, Masuda A, Iguchi Y, Udagawa T, Watanabe H, Katsuno M, Ohno K, Sobue G. FUS-regulated region- and cell-type-specific transcriptome is associated with cell selectivity in ALS/FTLD. Sci Rep. 2013;3:2388. PubMed.
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Brandeis University
The work seems carefully done, and the results are clearly presented. I also think it represents an important attempt to get at a central problem in neuodegenerative diseases in general (and ALS in particular): the issue of selective vulnerability. Take the SOD1-dependent form of ALS as an example: the SOD1 gene is expressed in every cell in the body, yet mutants cause the death of a subset of neurons, specifically the motor neurons. Why?
FUS is a good choice to study. Because FUS mutations lead to two somewhat distinct diseases, FTLD and ALS, one might naively expect that FUS-dependent genes could be similar in motor and cortical neurons, and distinct from, say, cerebellar neurons, and that's exactly what was found. The identity of some of the genes discovered was also interesting, though a number of them had already been turned up in other studies of FUS and TDP-43. But the fact that many are associated with other CNS disorders is probably not a coincidence.
That said, I have two concerns with this study: one specific, and one general. Specifically, they silenced FUS rather than looked at the effect of mutating it. I understand why they did that, because they wanted to know what genes FUS regulated. Still, doing it that way weakens the relevance of this work for human disease, because there is as yet no compelling evidence that it is a loss of FUS function in the nucleus that is responsible for neuronal death in FTLD and ALS, and tantalizing evidence that a toxic gain of function in the cytosol, which they do not address in this work, is the primary culprit (of course, it could be both).
Generally, studies like this, though I think they can be quite valuable, are based on the presumption that cataloging the interactions of a gene is crucial to understanding its role in disease. Maybe that's true. But maybe it isn't always true. I'd have liked this paper even more if they had thought of a way to do a focused, powerful experiment that directly addresses the question of selective vulnerability in disease. They don't really do that here. Their work might be very relevant to that question, and I hope it is, but in the end I, for one, am still left wondering why some neurons die and others don't.
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