SUMMARY For some neurological disorders, disease is primarily RNA-mediated due to expression of non-coding microsatellite expansion RNAs (RNAexp). Toxicity is thought to result from enhanced binding of proteins to these expansions and depletion from their normal cellular targets. However, experimental evidence for this sequestration model is lacking. Here, we use HITS-CLIP and pre-mRNA processing analysis of human control versus myotonic dystrophy (DM) brains to provide compelling evidence for this RNA toxicity model. MBNL2 binds directly to DM repeat expansions in the brain resulting in depletion from its normal RNA targets with downstream effects on alternative splicing and polyadenylation. Similar RNA processing defects were detected in Mbnl compound knockout mice, highlighted by dysregulation of Mapt splicing and fetal tau isoform expression in adults. These results demonstrate that MBNL proteins are directly sequestered by RNAexp in the DM brain and introduce a powerful experimental tool to evaluate RNA-mediated toxicity in other expansion diseases.

The white-spotted charr (Salvelinus leucomaenis) is a coldwater-adapted fish distributed in far-eastern Asia. To assess phylogeographic patterns of this species over most of its range in the Japanese archipelago and Sakhalin Island, Russia, we examined nucleotide sequences of the mitochondrial DNA (mtDNA) cytochrome b region (557 bp) in 141 individuals from 50 populations. A total of 33 (5.5%) nucleotide positions were polymorphic and defined 29 haplotypes. Phylogenetic analysis assigned the observed haplotypes to four main clades, which were characterized by the idiosyncrasies and discontinuity of geographic distributions. The nested clade analyses revealed that the geographical distribution patterns of some haplotypes and clades were explained by historical event such as past fragmentation. Although substantial genetic differentiation was found among the four main clades, their geographic distributions overlapped extensively in several regions. Since white-spotted charr can potentially use both freshwater and marine environments, coexistence among different lineages can be attributed to secondary contact through range expansion by migratory individuals during multiple glacial periods after interglacial isolation. Finally, our data demonstrate that the current subspecies designation does not reflect the phylogeography of this species based on mtDNA analysis. Hierarchical analysis (AMOVA) also showed that genetic variation was far more pronounced within subspecies than among subspecies (i.e., among discrete regions). These results suggest that each population, rather than each subspecies, must be treated as an evolutionarily significant unit.

Mucin-type glycoproteins are the major structural proteins in gastric mucus. Stomach mucin proteins include MUC5AC, synthesized by surface foveolar or pit cells, and MUC6, synthesized by neck and gland cells. The aim of this study was to determine the spatial distribution of these mucin proteins within the extracellular mucous coat. Double-labeling immunoflourescence/confocal microscopy was used in histologically normal surgical resection specimens. Intralumenal mucin within antral glands consisted entirely of MUC6 protein. Intralumenal mucin within the gland isthmus region consisted of an irregular mixture of MUC5AC and MUC6. The mucous layer on the gastric surface consisted primarily of MUC5AC extending in layered sheets with MUC6 protein layered in between. The laminated appearance of the surface mucus was present in both H. pylori-infected and noninfected specimens. These data indicate that MUC5AC and MUC6 proteins remain segregated within the mucous gel in a laminated linear arrangement. The physical stratification of mucin proteins may confer increased strength to the mucous layer or represent independent and redundant protection.

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