Abstract
Mutations in the RNA-binding protein FUS cause amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease. FUS plays a role in numerous aspects of RNA metabolism, including ...mRNA splicing. However, the impact of ALS-causative mutations on splicing has not been fully characterized, as most disease models have been based on overexpressing mutant FUS, which will alter RNA processing due to FUS autoregulation. We and others have recently created knockin models that overcome the overexpression problem, and have generated high depth RNA-sequencing on FUS mutants in parallel to FUS knockout, allowing us to compare mutation-induced changes to genuine loss of function. We find that FUS-ALS mutations induce a widespread loss of function on expression and splicing. Specifically, we find that mutant FUS directly alters intron retention levels in RNA-binding proteins. Moreover, we identify an intron retention event in FUS itself that is associated with its autoregulation. Altered FUS levels have been linked to disease, and we show here that this novel autoregulation mechanism is altered by FUS mutations. Crucially, we also observe this phenomenon in other genetic forms of ALS, including those caused by TDP-43, VCP and SOD1 mutations, supporting the concept that multiple ALS genes interact in a regulatory network.
Vivid colours found in living organisms are often the result of scattering from hierarchical nanostructures, where the interplay between order and disorder in their packing defines visual appearance. ...In the case of
IR1, the complex arrangement of the cells in polycrystalline three-dimensional lattices is found to be a distinctive fingerprint of colony organization. By combining analytical analysis of the angle-resolved scattering response of
bacterial colonies with numerical modelling, we show that we can assess the inter-cell distance and cell diameter with a resolution below 10 nm, far better than what can be achieved with conventional electron microscopy, suffering from preparation artefacts. Retrieving the role of disorder at different length scales from the salient features in the scattering response enables a precise understanding of the structural organization of the bacteria.
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