RAN proteins in neurodegenerative disease: Repeating themes and unifying therapeutic strategies

Microsatellite-expansion mutations cause >50 neurological diseases but there are no effective treatments. Mechanistic studies have historically focused on protein loss-of-function and protein or RNA gain-of-function effects. It is now clear that many expansion mutations are bidirectionally transcribed producing two toxic expansion RNAs, which can produce up to six mutant proteins by repeat associated non-AUG (RAN) translation. Multiple types of RAN proteins have been shown to be toxic in cell and animal models, to lead to common types of neuropathological changes, and to dysregulate key pathways. How RAN proteins are produced without the canonical AUG or close-cognate AUG-like initiation codons is not yet completely understood but RNA structure, flanking sequences and stress pathways have been shown to be important. Here, we summarize recent progress in understanding the role of RAN proteins, mechanistic insights into their production, and the identification of novel therapeutic strategies that may be applicable across these neurodegenerative disorders.     

A comparison of two class 10 pathogenesis-related genes from alfalfa and their activation by multiple stresses and stress-related signaling molecules

A collection of 29 pathogenesis-related 10 (PR10) genes of Medicago sativa and Medicago truncatula showed that they were almost all obtained from cDNA libraries of tissues undergoing abiotic or biotic stresses. The predicted proteins could be divided into two subclasses, PR10.1 and PR10.2, but in silico predicted models of their three-dimensional structures revealed that they could be further divided based on size of the hydrophobic internal cavity and number of β-bulges. A comparison of the expression of two highly similar M. sativa subclass PR10.1 genes, MsPR10.1A and MsPR10.1B, predicted to have similar sized hydrophobic internal cavities, but a different number of β-bulges revealed differences in their expression patterns. MsPR10.1A was induced faster than MsPR10.1B by ABA, ethylene, and X. campestris pv. alfalfae, but slower than MsPR10.1B by harvesting and wounding. Unlike MsPR10.1A, MsPR10.1B expression was induced in non-harvested tissues following harvesting, but was not induced by heat treatment. Histochemical observations of Nicotiana benthamiana transformed with 657 bp of the MsPR10.1A promoter fused to the β-glucuronidase (GUS) gene showed that GUS expression was wound-inducible in leaves, which was consistent with MsPR10.1A expression in alfalfa leaves. GUS expression in stems and leaves was mostly in vascular tissue. The MsPR10.1A promoter may be valuable in controlling the expression in vascular tissues and disease resistance.     

Unique features of transcription termination and initiation at closely spaced tandem human genes

The authors regret having omitted grant attributions in the original publication, and the acknowledgments are herewith updated.“This work was supported by grants to IU from the European Research Council (lncImpact project number 863589), the Abisch‐Frenkel Foundation for the Promotion of Life Sciences, and the Kekst Family Institute for Medical Genetics.”The authors apologize for this oversight and any confusion it may have caused.     

Molecular and functional profiling of Arabidopsis pathogenesis-related genes: insights into their roles in salt response of seed germination

Pathogenesis-related (PR) proteins are a group of heterogeneous proteins encoded by genes that are rapidly induced by pathogenic infections and by salicylic acid (SA), jasmonic acid (JA) and ethylene (ET). They are widely used as molecular markers for resistance response to pathogens and systemic acquired response (SAR). However, recent studies have shown that the PR genes are also regulated by environmental factors, including light and abiotic stresses, and by developmental cues, suggesting that they also play a role in certain stress responses and developmental processes. In this work, we systematically examined the expression patterns of Arabidopsis PR genes. We also investigated the effects of environmental stresses and growth hormones on the expression of PR genes. We found that individual PR genes are temporally and spatially regulated in distinct patterns. In addition, they are differentially regulated by plant growth hormones, including SA, ABA, JA, ET and brassinosteroid (BR), and by diverse abiotic stresses, supporting the contention that the PR proteins play a role in plant developmental processes other than disease resistance response. Interestingly, PR-3 was induced significantly by high salt in an ABA-dependent manner. Consistent with this, a T-DNA insertional knockout plant with disruption of the PR-3 gene showed a significantly reduced rate of seed germination in the presence of high salt. It is thus proposed that PR-3 mediates ABA-dependent salt stress signals that affect seed germination in Arabidopsis. PR-4 and PR-5 also contributed to salt regulation of seed germination, although their effects were not as evident as those of PR-3.     

Plant sigma factors and their role in plastid transcription

Plant sigma factors determine the promoter specificity of the major RNA polymerase of plastids and thus regulate the first level of plastome gene expression. In plants, sigma factors are encoded by a small family of nuclear genes, and it is not yet clear if the family members are functionally redundant or each paralog plays a particular role. The review presents the analysis of the information on plant sigma factors obtained since their discovery a decade ago and focuses on similarities and differences in structure and functions of various paralogs. Special attention is paid to their interaction with promoters, the regulation of their expression, and their role in the development of a whole plant. The analysis suggests that though plant sigma factors are basically similar, at least some of them perform distinct functions. Finally, the work presents the scheme of this gene family evolution in higher plants.