Advances in the Pathophysiology of Memory

Dear Colleagues,

The mechanisms of de novo gene expression and translation of specific gene transcripts have long been known to mediate long-lasting changes in synaptic plasticity and long-term memory.

To regulate the spatiotemporal synthesis of proteins, neurons must efficiently coordinate the transport and metabolism of mRNAs. Messenger ribonucleoprotein (mRNP) granules are dynamic, self-assembling structures that harbor repressed, non-translating mRNAs and transacting RNA binding proteins (RBPs) that regulate mRNA translation, localization, and turnover, in response to synaptic activity.

The analysis of mRNP granules in different contexts has revealed common themes of assembly, disassembly, and modes of mRNA regulation, yet new studies continue to reveal unexpected and important findings, such as links between aberrant mRNP granule assembly and neurodevelopmental and neurodegenerative disease.  Disease-causing mutations in mRNAs or RBPs in fact may lead to disruption of the mRNA packaging into granules and alter subsequent transport and translation as observed for Pumilio and FMRP proteins. Additionally, low complexity (LC) prion-like domains are over-represented among RBPs and contribute to the dynamic nature of RNA granules. Importantly, several neurodegenerative diseases are characterized by cytoplasmic “solid” aggregates formed by RBPs harboring LC prion-like domains, such as Tia, TDP43, FUS and hnRNPs. These pathological mechanisms underscore the importance of mRNA being in the right place at the right time, as well as the importance of mRNA as a structural platform to coordinate interactions between RBPs and associated proteins.

Despite the excellent existing literature, several key questions regarding mRNP granules remain to be addressed. First, 1) What is the complete RNA and protein composition of mRNP granules in the different districts present within neurons? 2) What are the molecular events that govern entry and exit of mRNAs to, from, and between mRNP granules, especially during learning and memory? 3) How do granules assemble and disassemble, and how are these processes affected in disease? Finally, what is the role of aggregation of various mRNP granules?

This Special Issue, therefore, focuses on reviews and original research articles that help gather further details on the cellular and molecular regulation of RBP in memory and in neurodegeneration.

There are numerous limitations in studying mRNA trafficking and translation in neurons, such as the lack of robust assays to determine the exact localization and timing of synthesized proteins. Moreover, most mRNPs transport processes have been studied in the context of nonphysiological stimuli, such as bath application of neurotransmitters in cellular cultures. As techniques for single synapse stimulation and single molecule imaging of mRNA in live tissue improve, we may observe different behavior of mRNA transport under more physiological stimulation paradigms. Continued study of these enigmatic structures thus promises fascinating new insights into neuronal function, and may also suggest novel therapeutic strategies in various disease states.

In this Special Issue, we are seeking submissions that address some of the questions raised above. We aim to bring together new research from different fields, like bioinformatics, biophysics, neurobiology, and neurodegeneration to provide a multidisciplinary evidence base for the importance of RBP in physiological and pathological aspects of brain function.

Dr. Luana Fioriti
Dr. Lenzie Ford
Guest Editors

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• mRNP granules
• local protein synthesis
• learning and memory
• prion-like domains
• aberrant aggregation
• neurodegeneration