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Dominantly inherited mutations in an endoplasmic reticulum protein called VAPB have been found in a subset of patients with a rare familial form of amyotrophic lateral sclerosis (ALS). In this issue, Tsuda et al. (2008) identify a secreted form of VAPB that binds directly to Eph receptors inducing their activation and signaling, providing fresh insights into ALS pathogenesis, including non-neuronal aspects of this disorder.

SummaryAlthough uridine-rich small nuclear RNAs (U-snRNAs) are essential for pre-mRNA splicing, little is known regarding their function in the regulation of alternative splicing or of the biological consequences of their dysfunction in mammals. Here, we demonstrate that mutation of Rnu2-8, one of the mouse multicopy U2 snRNA genes, causes ataxia and neurodegeneration. Coincident with the observed pathology, the level of mutant U2 RNAs was highest in the cerebellum and increased after granule neuron maturation. Furthermore, neuron loss was strongly dependent on the dosage of mutant and wild-type snRNA genes. Comprehensive transcriptome analysis identified a group of alternative splicing events, including the splicing of small introns, which were disrupted in the mutant cerebellum. Our results suggest that the expression of mammalian U2 snRNA genes, previously presumed to be ubiquitous, is spatially and temporally regulated, and dysfunction of a single U2 snRNA causes neuron degeneration through distortion of pre-mRNA splicing.