Familial forms of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal disease (FTD) have previously been linked with genes encoding FUS and TDP-43, although the molecular mechanisms underlying this association were previously unclear. Wang et al. used Drosophila, in which these proteins are conserved, to investigate the outcome of disrupting each of the genes that encode them. The data show that genetic disruption of Caz, the fly homologue of FUS, causes defects in locomotion and longevity, which could be rescued by human FUS, but not by ALS-associated mutated forms of FUS. Disruption of the gene encoding TBPH, the fly homologue of TDP-43, had similar but more marked effects on fly locomotion and lifespan. Furthermore, rescue experiments showed that Caz and TBPH act in a common pathway. Overexpression experiments did not support a gain-of-function activity for these proteins in disease pathology. Rather, the data support the idea that loss of function of a common molecular process that requires FUS and TDP-43 contributes to disease.

J. R.
N. A.
B. D.
The ALS-associated proteins FUS and TDP-43 function together to affect Drosophila locomotion and life span
J. Clin. Invest.

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