@article {35149, title = {RNP-Granule Assembly via Ataxin-2 Disordered Domains Is Required for Long-Term Memory and Neurodegeneration.}, journal = {Neuron}, volume = {98}, year = {2018}, month = {2018 May 16}, pages = {754-766.e4}, abstract = {

Human Ataxin-2 is implicated in the cause and progression of amyotrophic lateral sclerosis (ALS) and type 2 spinocerebellar ataxia (SCA-2). In Drosophila, a conserved atx2 gene is essential for animal survival as well as for normal RNP-granule assembly, translational control, and long-term habituation. Like its human homolog, Drosophila Ataxin-2 (Atx2) contains polyQ repeats and additional intrinsically disordered regions (IDRs). We demonstrate that Atx2 IDRs, which are capable of mediating liquid-liquid phase transitions in\ vitro, are essential for efficient formation of neuronal mRNP assemblies in\ vivo. Remarkably, ΔIDR mutants that lack neuronal RNP granules show normal animal development, survival, and fertility. However, they show defects in long-term memory formation/consolidation as well as in C9ORF72 dipeptide repeat or FUS-induced neurodegeneration. Together, our findings demonstrate (1) that higher-order mRNP assemblies contribute to long-term neuronal plasticity and memory, and (2) that a targeted reduction in RNP-granule formation efficiency can alleviate specific forms of neurodegeneration.

}, issn = {1097-4199}, doi = {10.1016/j.neuron.2018.04.032}, author = {Bakthavachalu, Baskar and Huelsmeier, Joern and Sudhakaran, Indulekha P and Hillebrand, Jens and Singh, Amanjot and Petrauskas, Arnas and Thiagarajan, Devasena and Sankaranarayanan, M and Mizoue, Laura and Anderson, Eric N and Pandey, Udai Bhan and Ross, Eric and VijayRaghavan, K and Parker, Roy and Ramaswami, Mani} } @article {26664, title = {Long-term memory consolidation: The role of RNA-binding proteins with prion-like domains.}, journal = {RNA Biol}, volume = {14}, year = {2017}, month = {2017 May 04}, pages = {568-586}, abstract = {

Long-term and short-term memories differ primarily in the duration of their retention. At a molecular level, long-term memory (LTM) is distinguished from short-term memory (STM) by its requirement for new gene expression. In addition to transcription (nuclear gene expression) the translation of stored mRNAs is necessary for LTM formation. The mechanisms and functions for temporal and spatial regulation of mRNAs required for LTM is a major contemporary problem, of interest from molecular, cell biological, neurobiological and clinical perspectives. This review discusses primary evidence in support for translational regulatory events involved in LTM and a model in which different phases of translation underlie distinct phases of consolidation of memories. However, it focuses largely on mechanisms of memory persistence and the role of prion-like domains in this defining aspect of long-term memory. We consider primary evidence for the concept that Cytoplasmic Polyadenylation Element Binding (CPEB) protein enables the persistence of formed memories by transforming in prion-like manner from a soluble monomeric state to a self-perpetuating and persistent polymeric translationally active state required for maintaining persistent synaptic plasticity. We further discuss prion-like domains prevalent on several other RNA-binding proteins involved in neuronal translational control underlying LTM. Growing evidence indicates that such RNA regulatory proteins are components of mRNP (RiboNucleoProtein) granules. In these proteins, prion-like domains, being intrinsically disordered, could mediate weak transient interactions that allow the assembly of RNP granules, a source of silenced mRNAs whose translation is necessary for LTM. We consider the structural bases for RNA granules formation as well as functions of disordered domains and discuss how these complicate the interpretation of existing experimental data relevant to general mechanisms by which prion-domain containing RBPs function in synapse specific plasticity underlying LTM.

}, issn = {1555-8584}, doi = {10.1080/15476286.2016.1244588}, author = {Sudhakaran, Indulekha P and Ramaswami, Mani} } @article {11592, title = {Dysregulation of mRNA Localization and Translation in Genetic Disease.}, journal = {J Neurosci}, volume = {36}, year = {2016}, month = {2016 Nov 09}, pages = {11418-11426}, abstract = {

RNA-binding proteins (RBPs) acting at various steps in the post-transcriptional regulation of gene expression play crucial roles in neuronal development and synaptic plasticity. Genetic mutations affecting several RBPs and associated factors lead to diverse neurological symptoms, as characterized by neurodevelopmental and neuropsychiatric disorders, neuromuscular and neurodegenerative diseases, and can often be multisystemic diseases. We will highlight the physiological roles of a few specific proteins in molecular mechanisms of cytoplasmic mRNA regulation, and how these processes are dysregulated in genetic disease. Recent advances in computational biology and genomewide analysis, integrated with diverse experimental approaches and model systems, have provided new insights into conserved mechanisms and the shared pathobiology of mRNA dysregulation in disease. Progress has been made to understand the pathobiology of disease mechanisms for myotonic dystrophy, spinal muscular atrophy, and fragile X syndrome, with broader implications for other RBP-associated genetic neurological diseases. This gained knowledge of underlying basic mechanisms has paved the way to the development of therapeutic strategies targeting disease mechanisms.

}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.2352-16.2016}, author = {Wang, Eric T and Taliaferro, J Matthew and Lee, Ji-Ann and Sudhakaran, Indulekha P and Rossoll, Wilfried and Gross, Christina and Moss, Kathryn R and Bassell, Gary J} }