Recoding: reprogrammed genetic decoding with an emphasis on antizyme regulatory frameshifting

Recoding embraces mechanisms that augment the rules of standard genetic decoding. The deviations from standard decoding are often purposeful and their realisation provides diverse and flexible regulatory mechanisms. Recoding events such as programed ribosomal frameshifting are especially plentiful in viruses. In most organisms only a few cellular genes are known to employ programed ribosomal frameshifting in their expression. By far the most prominent and therefore well-studied case of cellular +1 frameshifting is in expression of antizyme mRNAs. The protein antizyme is a key regulator of polyamine levels in most eukaryotes with some exceptions such as plants. A +1 frameshifting event is required for the full length protein to be synthesized and this requirement is a conserved feature of antizyme mRNAs from yeast to mammals. The efficiency of the frameshifting event is dependent on the free polyamine levels in the cell. cis-acting elements in antizyme mRNAs such as specific RNA structures are required to stimulate the frameshifting efficiency. Here I describe a novel stimulator of antizyme +1 frameshifting in the Agaricomycotina class of Basidiomycete fungi. It is a nascent peptide that acts from within the ribosome exit tunnel to stimulate frameshifting efficiency in response to polyamines. The interactions of the nascent peptide with components of the peptidyl transferase centre and the protein exit tunnel emerge in our understanding as powerful means which the cell employs for monitoring and tuning the translational process. These interactions can modulate the rate of translation, protein cotranslational folding and localization. Some nascent peptides act in concert with small molecules such as polyamines or antibiotics to stall the ribosome. To these known nascent peptide effects we have added that of a stimulatory effect on the +1 frameshifting in antizyme mRNAs. It is becoming evident that nascent peptide involvement in regulation of translation is a much more general phenomenon than previously anticipated.

Cognitive dysfunction in Duchenne muscular dystrophy: a possible role for neuromodulatory immune molecules

Duchenne muscular dystrophy (DMD) is an X chromosome-linked disease characterized by progressive physical disability, immobility, and premature death in affected boys. Underlying the devastating symptoms of DMD is the loss of dystrophin, a structural protein that connects the extracellular matrix to the cell cytoskeleton and provides protection against contraction-induced damage in muscle cells, leading to chronic peripheral inflammation. However, dystrophin is also expressed in neurons within specific brain regions, including the hippocampus, a structure associated with learning and memory formation. Linked to this, a subset of boys with DMD exhibit nonprogressing cognitive dysfunction, with deficits in verbal, short-term, and working memory. Furthermore, in the genetically comparable dystrophin-deficient mdx mouse model of DMD, some, but not all, types of learning and memory are deficient, and specific deficits in synaptogenesis and channel clustering at synapses has been noted. Little consideration has been devoted to the cognitive deficits associated with DMD compared with the research conducted into the peripheral effects of dystrophin deficiency. Therefore, this review focuses on what is known about the role of full-length dystrophin (Dp427) in hippocampal neurons. The importance of dystrophin in learning and memory is assessed, and the potential importance that inflammatory mediators, which are chronically elevated in dystrophinopathies, may have on hippocampal function is also evaluated.