The Ataxin-2 protein is required for microRNA function and synapse-specific long-term olfactory habituation

McCann, Cathal T.; Holohan, Eimear E.; Das, Sudeshna; Dervan, Adrian; Larkin, Aoife; Lee, John Anthony; Rodrigues, Veronica; Parker, Roy; Ramaswami, Mani

doi:10.1073/pnas.1107198108

Cited by 152 publications

(167 citation statements)

References 62 publications

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“…Interesting candidates are Atx2 and FMRP, both of which are RNA-granule proteins, involved in neuronal translational control and preferentially required for long-term memory formation. 85,86,[200][201][202] Algorithms that are designed to detect prion like Q/N domains identify both Atx2 and FMRP as prion like domain containing proteins. 160,166,184,203 We suggest alternative models for how these proteins could function, being aware not only that these models represent extreme and not mutually exclusive positions when intermediate and compromise positions are tenable, but also that different RBPs may differ in their mechanism of action.…”

Section: Resultsmentioning

confidence: 99%

“…Consistently several neuronal RNA-granule components such as Ataxin2, Staufen and FMRP have been shown to be required for long-term memory formation as well. 85,86,[183][184][185] Prion-like domains may regulate RNA granule assembly…”

Section: Prion Like Domains In Neuronal Rnp Mediated Translationmentioning

confidence: 99%

“…83,84 Consistent with these results RNP components are also found to associate with and regulate the translation of CaMKII in a manner required for LTM. 74,85,86 In addition to RBPs, neuronal mRNA translation is regulated by non coding RNAs such as microRNAs (miRNAs) that are abundant in brain tissue. 87 miRNA association with mRNAs by virtue of miRNA binding sites on 3-UTR can induce translational repression as well as promote the localization of RNAs to processing bodies.…”

Section: Rna Regulation Is Central To Long-term Memory Formationmentioning

confidence: 99%

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Long-term memory consolidation: The role of RNA-binding proteins with prion-like domains

Sudhakaran

Ramaswami

2016

RNA Biology

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Prion Like Domains In Neuronal Rnp Mediated Translationmentioning

confidence: 99%

Section: Rna Regulation Is Central To Long-term Memory Formationmentioning

confidence: 99%

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Long-term memory consolidation: The role of RNA-binding proteins with prion-like domains

Sudhakaran

Ramaswami

2016

RNA Biology

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“…Here, a simple Atx2-dependent form of long-term memory, long-term habituation (LTH), arises from the plasticity of inhibitory transmission between two cell types, local circuit interneurons (LNs) and output projection neurons (PNs) (31,46,47). This potentially allows us to ask whether dFmr1 and Atx2 function in the same cells for LTH formation.…”

mentioning

confidence: 99%

“…First, both proteins are candidate RNAbinding proteins, with Atx2 having the like SM (LSM) domain and dFmr1 having the K homology (KH) domain that mediates RNA binding (28)(29)(30), and are implicated in the microRNA (miRNA) pathway (16,(31)(32)(33)(34)(35). Second, in cultured cells, both proteins are present on cytoplasmic mRNP aggregates (36)(37)(38)(39)(40)(41)(42); and third, recent work in Drosophila indicates that both proteins may function in the consolidation of different forms of longterm memory (LTM) (16,31,(43)(44)(45). These observations lead to several important questions.…”

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confidence: 99%

FMRP and Ataxin-2 function together in long-term olfactory habituation and neuronal translational control

Sudhakaran

Hillebrand

Dervan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Fragile X mental retardation protein (FMRP) and Ataxin-2 (Atx2) are triplet expansion disease-and stress granule-associated proteins implicated in neuronal translational control and microRNA function. We show that Drosophila FMRP (dFMR1) is required for long-term olfactory habituation (LTH), a phenomenon dependent on Atx2-dependent potentiation of inhibitory transmission from local interneurons (LNs) to projection neurons (PNs) in the antennal lobe. dFMR1 is also required for LTH-associated depression of odor-evoked calcium transients in PNs. Strong transdominant genetic interactions among dFMR1, atx2, the deadbox helicase me31B, and argonaute1 (ago1) mutants, as well as coimmunoprecitation of dFMR1 with Atx2, indicate that dFMR1 and Atx2 function together in a microRNA-dependent process necessary for LTH. Consistently, PN or LN knockdown of dFMR1, Atx2, Me31B, or the miRNA-pathway protein GW182 increases expression of a Ca2+/calmodulin-dependent protein kinase II (CaMKII) translational reporter. Moreover, brain immunoprecipitates of dFMR1 and Atx2 proteins include CaMKII mRNA, indicating respective physical interactions with this mRNA. Because CaMKII is necessary for LTH, these data indicate that fragile X mental retardation protein and Atx2 act via at least one common target RNA for memory-associated long-term synaptic plasticity. The observed requirement in LNs and PNs supports an emerging view that both presynaptic and postsynaptic translation are necessary for long-term synaptic plasticity. However, whereas Atx2 is necessary for the integrity of dendritic and somatic Me31B-containing particles, dFmr1 is not. Together, these data indicate that dFmr1 and Atx2 function in long-term but not short-term memory, regulating translation of at least some common presynaptic and postsynaptic target mRNAs in the same cells.synapse plasticity | olfactory memory | neural circuits | neurological disease

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Drosophila ataxin‐2 gene encodes two differentially expressed isoforms and its function in larval fat body is crucial for development of peripheral tissues

et al. 2016

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Different isoforms of ataxin‐2 are predicted in Drosophila and may underlie different cellular processes. Here, we validated the isoforms B and C of Drosophila ataxin‐2 locus (dAtx2), which we found to be expressed in various tissues and at different levels during development. dAtx2‐B mRNA was detected at low amounts during all developmental stages, whereas dAtx2‐C mRNA levels increase by eightfold from L3 to pupal–adult stages. Higher amounts of dAtx2‐B protein were detected in embryos, while dAtx2‐C protein was also expressed in higher levels in pupal–adult stages, indicating post‐transcriptional control for isoform B and transcription induction for isoform C, respectively. Moreover, in the fat body of L3 larvae dAtx2‐C, but not dAtx2‐B, accumulates in cytoplasmic foci that colocalize with sec23, a marker of endoplasmic reticulum exit sites (ERES). Interestingly, animals subjected to selective knockdown of dAtx2 in the larval fat body do not complete metamorphosis and die at the third larval stage or early puparium. Additionally, larvae knocked down for dAtx2, grown at 29 °C, are significantly smaller than control animals due to reduction in DNA replication and cell growth, which are consistent with the decreased levels of phosphorylated‐AKT observed in the fat body. Based on the localization of ataxin‐2 (dAtx2‐C) in ERESs, and on the phenotypes observed by dAtx2 knockdown in the larval fat body, we speculate a possible role for this protein in processes that regulate ERES formation. These data provide new insights into the biological function of ataxin‐2 with potential relevance to neurodegenerative diseases.

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The Ataxin-2 protein is required for microRNA function and synapse-specific long-term olfactory habituation

Cited by 152 publications

References 62 publications

Long-term memory consolidation: The role of RNA-binding proteins with prion-like domains

Long-term memory consolidation: The role of RNA-binding proteins with prion-like domains

FMRP and Ataxin-2 function together in long-term olfactory habituation and neuronal translational control

Drosophila ataxin‐2 gene encodes two differentially expressed isoforms and its function in larval fat body is crucial for development of peripheral tissues

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