Pre-mRNA splicing in higher plants.

P re-mRNA splicing is one of the fundamental processes in constitutive and regulated gene expression in eukaryotes. During splicing, introns present in primary gene transcripts are removed and exons are ligated to produce translationally competent mRNAs. The basic mechanism of intron excision is similar in all eukaryotes. The reaction is mediated by the spliceosome, a large ribonucleoprotein (RNP) complex, which is assembled anew at each intron from small nuclear RNP particles (U-snRNPs) and numerous protein factors. Spliceosome assembly is a highly ordered and dynamic reaction, involving hydrolysis of several ATP molecules and many structural rearrangements Properties of plant introns The intron and exon organization of higher plant genes is similar to that of vertebrates In spite of these similarities, the requirements for intron recognition in plants differ from those in other eukaryotes, and plant cells generally fail to splice heterologous pre-mRNAs. The most important difference is a strong compositional bias for UA-or U-rich sequences in plant introns compared with those from yeast and vertebrates U12-type introns A minor class of nuclear pre-mRNA introns, referred to as U12-type or AT-AC introns (because they frequently start with AT and terminate with AC) have recently been described 3,13 . These introns contain different splice site and branch point sequences, and are excised by an alternative U12-type spliceosom

UBA1 and UBA2, Two Proteins That Interact with UBP1, a Multifunctional Effector of Pre-mRNA Maturation in Plants

Nicotiana plumbaginifolia UBP1 is an hnRNP-like protein associated with the poly(A)(+) RNA in the cell nucleus. Consistent with a role in pre-mRNA processing, overexpression of UBP1 in N. plumabaginifolia protoplasts enhances the splicing of suboptimal introns and increases the steady-state levels of reporter mRNAs, even intronless ones. The latter effect of UBP1 is promoter specific and appears to be due to UBP1 binding to the 3′ untranslated region (3′-UTR) and protecting the mRNA from exonucleolytic degradation (M. H. L. Lambermon, G. G. Simpson, D. A. Kirk, M. Hemmings-Mieszczak, U. Klahre, and W. Filipowicz, EMBO J. 19:1638-1649, 2000). To gain more insight into UBP1 function in pre-mRNA maturation, we characterized proteins interacting with N. plumbaginifolia UBP1 and one of its Arabidopsis thaliana counterparts, AtUBP1b, by using yeast two-hybrid screens and in vitro pull-down assays. Two proteins, UBP1-associated proteins 1a and 2a (UBA1a and UBA2a, respectively), were identified in A. thaliana. They are members of two novel families of plant-specific proteins containing RNA recognition motif-type RNA-binding domains. UBA1a and UBA2a are nuclear proteins, and their recombinant forms bind RNA with a specificity for oligouridylates in vitro. As with UBP1, transient overexpression of UBA1a in protoplasts increases the steady-state levels of reporter mRNAs in a promoter-dependent manner. Similarly, overexpression of UBA2a increases the levels of reporter mRNAs, but this effect is promoter independent. Unlike UBP1, neither UBA1a nor UBA2a stimulates pre-mRNA splicing. These and other data suggest that UBP1, UBA1a, and UBA2a may act as components of a complex recognizing U-rich sequences in plant 3′-UTRs and contributing to the stabilization of mRNAs in the nucleus

Cyclohexanehexol inhibitors of Aβ aggregation prevent and reverse Alzheimer phenotype in a mouse model

When given orally to a transgenic mouse model of Alzheimer disease, cyclohexanehexol stereoisomers inhibit aggregation of amyloid β peptide (Aβ) into high-molecular-weight oligomers in the brain and ameliorate several Alzheimer disease-like phenotypes in these mice, including impaired cognition, altered synaptic physiology, cerebral Aβ pathology and accelerated mortality. These therapeutic effects, which occur regardless of whether the compounds are given before or well after the onset of the Alzheimer disease-like phenotype, support the idea that the accumulation of Aβ oligomers has a central role in the pathogenesis of Alzheimer disease