| Abstrakt: |
Post-transcriptional control in the cytoplasm is an important arm of gene expression. Regulation of messenger RNAs (mRNAs) largely occurs in specialized structures collectively termed RNA granules. These large ribonucleoproteins are microscopically visible, although hard to purify biochemically, and are believed to serve as the functional units for mRNA transport, storage, repression and decay. It was during the study of mRNA cytoplasmic transport, a few decades ago, that RNA granules were identified by several groups. Current evidence indicates that this level of supramolecular organization is not restricted to complex vertebrate cells, but it is rather a widespread phenomenon. The presence of RNA granules involved in several functions has been reported in highly differentiated cells as well as simple unicellular organisms, ranging from trypanosomatids and yeast, to insect and vertebrate oocytes and neurons. In the latter cell type, both the somatodendritic compartment and the axon are loaded with a plethora of RNA granules of distinct composition. RNA granules are believed to self-assemble to coordinate the translational activation, subcellular localization and silencing of mRNAs with a common fate. More recent is the discovery of RNA granules specific to the stress response, which is a complex cell reaction to ensure survival upon noxious conditions. During acute stress, the assembly of the so-called Stress Granules (SGs) takes place. Evidence has been adduced that SGs help remodeling of the translational apparatus to allow translation of protective molecules, although they do not control the global translational silencing triggered by cell stress. SGs are related to another kind of RNA granules, termed Processing Bodies (PBs). SGs and PBs are referred to as mRNA silencing foci, as they harbor mRNAs that are not being translated. Similar structures exist in unicellular organisms where gene expression is regulated mostly at the post-transcriptional level. This series of mini-reviews on RNA granules in health and disease focus on hot topics that highlight the relevance of RNA granules in distinct cell types and processes. In the chapter entitled “Common themes in RNA subcellular transport, stress granule formation and abnormal protein aggregation”, Bensenor and co-workers summarize the mechanisms for mRNA transport and localization, which are operative in embryos and somatic cells. RNA transport granules contain several RNA binding proteins that are obligate SG components. In addition, SGs share common features with aggresomes and other abnormal protein aggregates associated to neurodegeneration. The presence of aggregates containing the SG components TAR DNA-binding protein (TDP-43) or Fused-in-Sarcoma/Translocated-in-Liposarcoma (FUS/TLS) is a pathological hallmark of frontotemporal lobar degeneration (FTLD), Amyotrophic Lateral Sclerosis (ALS) and Alzheimers disease. The shared presence of the aforementioned SG components, as well as additional functional similarities between these cytoplasmic aggregates are herein described. Current and future findings will open new avenues of research aimed to understand the relevance of SGs in the pathogenesis of these diseases. In the chapter focused on “RNA Metabolism in Neurodegenerative Diseases”, Volkening and Strong summarize the specific role of RNA granules on RNA regulation in mammalian neurons and discuss in which way recently described mutations in TDP-43 and FUS/TLS, contribute to ALS and FTLD by altering the normal metabolism of specific RNA molecules. The field is flourishing and future research will yield light on the affected cellular machineries, thus helping the design of therapies to handle each particular disease mechanism. Arguing a widespread accepted idea, mRNA translation is also important in the axon, which comprises a relative large fraction of the total neuronal cell volume. Addressing this intriguing aspect of RNA regulation in neurons, Canclini and co-workers focused on “The axonal transcriptome: RNA localization and function”. Their review highlights the fact that regulation of local translation at the axon involves specific RNA granules, and emphasizes the need of motor-mediated transport and the participation of micro RNAs. Evidence is presented that a number of RNAs in peripheral axons are apparently derived from neighboring glial cells, and this is particularly intriguing during axon regeneration after nerve injury. Finally, Casolas section -“RNA Granules Living a Post-transcriptional Life: the Trypanosomes Case”- is focused on the metabolism of RNA in trypanosomes. These organisms are the etiological agent of Chagas and Sleeping Sickness Diseases, which represent an important jeopardy for human health worldwide. This chapter summarizes how gene expression in trypanosomes is controlled mostly by mRNA degradation, silencing and translation repression. Not surprisingly, these processes involve the participation of a number of macromolecular aggregates related in composition and function to SGs, PBs and RNA granules from higher eukaryotes. However, the speculation is that subtle differences will help to develop rationale therapies to attack the parasites with minimal damage to the host cell. |
