Hruska-Plochan M, Wiersma VI, Betz KM, Mallona I, Ronchi S, Maniecka Z, Hock EM, Tantardini E, Laferriere F, Sahadevan S, Hoop V, Delvendahl I, Pérez-Berlanga M, Gatta B, Panatta M, van der Bourg A, Bohaciakova D, Sharma P, De Vos L, Frontzek K, Aguzzi A, Lashley T, Robinson MD, Karayannis T, Mueller M, Hierlemann A, Polymenidou M. A model of human neural networks reveals NPTX2 pathology in ALS and FTLD. Nature. 2024 Feb;626(8001):1073-1083. Epub 2024 Feb 14 PubMed.
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International Centre for Genetic Engineering and Biotechnology
One great drawback when studying proteins like TDP-43 is the incredible number of genes whose expression is controlled by this protein, and which become misregulated following TDP-43 aggregation in pathological conditions. From a therapeutic point of view, this observation raises the question as to whether it will be necessary to rescue all or most of these misregulated genes in order to prevent neuronal death, or whether it might be sufficient to focus on just a handful of key genes.
Using state-of-the-art approaches, the Polymenidou lab has shown that a single factor, called NPTX2, may be responsible for much of the toxicity displayed by TDP-43 loss of function in the nucleus. This exciting result suggests that many misregulated events can probably be compensated for by cellular mechanisms. Therefore, from a therapeutic point of view, it might be advantageous to focus on a set of key factors such as UNC13A, STMN2 and now, of course, NPTX2, and let the rest take care of themselves. Or, to paraphrase a quote from Gorge Orwell’s Animal Farm: “In neurodegeneration, all consequences of TDP-43 aggregation are equal, but some are more equal than others.”
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