The role of GPI-anchored PrP C in mediating the neurotoxic effect of scrapie prions in neurons.

There are two central phenomena in prion disease: prion replication and prion neurotoxicity. Underlying them both is the conversion of a host-encoded ubiquitously expressed protein, prion protein (PrP(C)), into a partially-protease resistant isoform, PrP(Sc), which accumulates in the brain. PrP(Sc) is associated with both pathology and infectivity. In the absence of PrP(C), PrP(Sc) cannot be generated and PrP-null mice do not propagate infectivity or develop pathology on infection with scrapie. However, while PrP(C) expression is fundamental to both prion infectivity and neurodegeneration, the uncoupling of these processes is a growing concept in the field. This dissociation is evident in subclinical states of prion infection, where PrP(Sc) levels are high in the absence of disease, and in transgenic mice experiments, where, despite extra-neuronal PrP(Sc) accumulation, even in very high amounts, there is no neurotoxicity. Both these models have further implications. Thus depleting PrP(C) from neurons (but not glia) of prion-infected mice prevents clinical disease, and detaching it from the surface of cells by removing its anchor does the same. The uncoupling toxicity and infectivity has implications for the nature of the neurotoxic species; these mouse models suggest that the site for the generation of this species is intra-neuronal. This review considers the role of neuronal surface-expressed PrP(C) in mediating toxicity in prion infection, and the dissociation of this from the deposition of PrP(Sc).

Translational control by cytoplasmic polyadenylation in Xenopus oocytes.

Elongation of the poly(A) tails of specific mRNAs in the cytoplasm is a crucial regulatory step in oogenesis and early development of many animal species. The best studied example is the regulation of translation by cytoplasmic polyadenylation elements (CPEs) in the 3' untranslated region of mRNAs involved in Xenopus oocyte maturation. In this review we discuss the mechanism of translational control by the CPE binding protein (CPEB) in Xenopus oocytes as follows: 1. The cytoplasmic polyadenylation machinery such as CPEB, the subunits of cleavage and polyadenylation specificity factor (CPSF), symplekin, Gld-2 and poly(A) polymerase (PAP). 2. The signal transduction that leads to the activation of CPE-mediated polyadenylation during oocyte maturation, including the potential roles of kinases such as MAPK, Aurora A, CamKII, cdk1/Ringo and cdk1/cyclin B. 3. The role of deadenylation and translational repression, including the potential involvement of PARN, CCR4/NOT, maskin, pumilio, Xp54 (Ddx6, Rck), other P-body components and isoforms of the cap binding initiation factor eIF4E. Finally we discuss some of the remaining questions regarding the mechanisms of translational regulation by cytoplasmic polyadenylation and give our view on where our knowledge is likely to be expanded in the near future.

Translational control of maskin mRNA by its 3' untranslated region.

BACKGROUND INFORMATION: Maskin is a member of the TACC (transforming acidic coiled-coil) domain proteins found in Xenopus laevis oocytes and embryos. It has been implicated in the co-ordination of the spindle and has been reported to mediate translational repression of cyclin B1 mRNA. RESULTS: In the present study, we report that maskin mRNA is translationally repressed at the level of initiation in stage 4 oocytes and becomes activated in stage 6 oocytes. The translational repression of maskin mRNA correlates with the presence of a short poly(A) tail on this mRNA in stage 4 oocytes. The 3'-UTR (untranslated region) of maskin can confer the translational regulation to a reporter mRNA, and so can the 3'-UTR of human TACC3. A conserved GUCU repeat element was found to repress translation in both stage 4 and stage 6 oocytes, but deletion of this element did not abrogate repression in stage 4 oocytes. UV cross-linking experiments indicated that overlapping sets of proteins bind efficiently to both the maskin and the cyclin B1 3'-UTRs. As reported previously, CPEB [CPE (cytoplasmic polyadenylation element)-binding protein] binds to the cyclin B1 3'-UTR, but its binding to the maskin 3'-UTR is minimal. By RNA affinity chromatography and MS, we identified the EDEN-BP [EDEN (embryonic deadenylation element)-binding protein] as one of the proteins binding to both the maskin and the cyclin B1 3'-UTRs. CONCLUSIONS: Maskin mRNA is translationally regulated by at least two repressor elements and an activation element. One of the repessor elements is the evolutionarily conserved GUCU repeat. EDEN-BP binds to both the maskin and cyclin B1 3'-UTRs, indicating it may be involved in the deadenylation of these mRNAs.