Showing papers by "Gerhard Schratt published in 2015"
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TL;DR: Ube3a1 RNA, a transcript that encodes a truncated U be3a protein lacking catalytic activity, prevents exuberant dendrite growth and promotes spine maturation in rat hippocampal neurons and defines a noncoding function of an alternative Ube3A transcript in dendritic protein synthesis, with potential implications for Angelman syndrome and ASD.
Abstract: The E3 ubiquitin ligase Ube3a is an important regulator of activity-dependent synapse development and plasticity. Ube3a mutations cause Angelman syndrome and have been associated with autism spectrum disorders (ASD). However, the biological significance of alternative Ube3a transcripts generated in mammalian neurons remains unknown. We report here that Ube3a1 RNA, a transcript that encodes a truncated Ube3a protein lacking catalytic activity, prevents exuberant dendrite growth and promotes spine maturation in rat hippocampal neurons. Surprisingly, Ube3a1 RNA function was independent of its coding sequence but instead required a unique 3' untranslated region and an intact microRNA pathway. Ube3a1 RNA knockdown increased activity of the plasticity-regulating miR-134, suggesting that Ube3a1 RNA acts as a dendritic competing endogenous RNA. Accordingly, the dendrite-growth-promoting effect of Ube3a1 RNA knockdown in vivo is abolished in mice lacking miR-134. Taken together, our results define a noncoding function of an alternative Ube3a transcript in dendritic protein synthesis, with potential implications for Angelman syndrome and ASD.
93 citations
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TL;DR: It is suggested that miR-137 is a key factor in the control of synaptic efficacy and mGluR-dependent synaptic plasticity, supporting the notion that glutamatergic dysfunction contributes to the pathogenesis of miR -137-linked cognitive impairments.
82 citations
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TL;DR: The results strongly suggest a causative role of rare SHANK2 variants in SCZ and underline the contribution of SHank2 gene mutations in a variety of neuropsychiatric disorders.
Abstract: Recent genetic data on schizophrenia (SCZ) have suggested that proteins of the postsynaptic density of excitatory synapses have a role in its etiology. Mutations in the three SHANK genes encoding for postsynaptic scaffolding proteins have been shown to represent risk factors for autism spectrum disorders and other neurodevelopmental disorders. To address if SHANK2 variants are associated with SCZ, we sequenced SHANK2 in 481 patients and 659 unaffected individuals. We identified a significant increase in the number of rare (minor allele frequency<1%) SHANK2 missense variants in SCZ individuals (6.9%) compared with controls (3.9%, P=0.039). Four out of fifteen non-synonymous variants identified in the SCZ cohort (S610Y, R958S, P1119T and A1731S) were selected for functional analysis. Overexpression and knockdown-rescue experiments were carried out in cultured primary hippocampal neurons with a major focus on the analysis of morphological changes. Furthermore, the effect on actin polymerization in fibroblast cell lines was investigated. All four variants revealed functional impairment to various degrees, as a consequence of alterations in spine volume and clustering at synapses and an overall loss of presynaptic contacts. The A1731S variant was identified in four unrelated SCZ patients (0.83%) but not in any of the sequenced controls and public databases (P=4.6 × 10−5). Patients with the A1731S variant share an early prodromal phase with an insidious onset of psychiatric symptoms. A1731S overexpression strongly decreased the SHANK2-Bassoon-positive synapse number and diminished the F/G-actin ratio. Our results strongly suggest a causative role of rare SHANK2 variants in SCZ and underline the contribution of SHANK2 gene mutations in a variety of neuropsychiatric disorders.
67 citations
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University of Bonn1, University of Marburg2, Forschungszentrum Jülich3, Ludwig Maximilian University of Munich4, Heidelberg University5, Aarhus University6, University of Basel7, German Center for Neurodegenerative Diseases8, Goethe University Frankfurt9, Max Planck Society10, University of Liverpool11, Dresden University of Technology12, University of Tübingen13, University of Duisburg-Essen14, University of Cologne15, Poznan University of Medical Sciences16, Nofer Institute of Occupational Medicine17, International Agency for Research on Cancer18, Black Dog Institute19, University of New South Wales20, Neuroscience Research Australia21, QIMR Berghofer Medical Research Institute22, Russian Academy23, Kursk State Medical University24, Russian Academy of Sciences25, Bashkir State University26, National Institutes of Health27, Dalhousie University28, Montreal Neurological Institute and Hospital29, McGill University30, Université du Québec à Chicoutimi31
TL;DR: In this article, gene-based analyses were performed for all known autosomal microRNAs using the largest genome-wide association data set of bipolar disorder to date (9747 patients and 14278 controls).
Abstract: Bipolar disorder (BD) is a severe and highly heritable neuropsychiatric disorder with a lifetime prevalence of 1%. Molecular genetic studies have identified the first BD susceptibility genes. However, the disease pathways remain largely unknown. Accumulating evidence suggests that microRNAs, a class of small noncoding RNAs, contribute to basic mechanisms underlying brain development and plasticity, suggesting their possible involvement in the pathogenesis of several psychiatric disorders, including BD. In the present study, gene-based analyses were performed for all known autosomal microRNAs using the largest genome-wide association data set of BD to date (9747 patients and 14 278 controls). Associated and brain-expressed microRNAs were then investigated in target gene and pathway analyses. Functional analyses of miR-499 and miR-708 were performed in rat hippocampal neurons. Ninety-eight of the six hundred nine investigated microRNAs showed nominally significant P-values, suggesting that BD-associated microRNAs might be enriched within known microRNA loci. After correction for multiple testing, nine microRNAs showed a significant association with BD. The most promising were miR-499, miR-708 and miR-1908. Target gene and pathway analyses revealed 18 significant canonical pathways, including brain development and neuron projection. For miR-499, four Bonferroni-corrected significant target genes were identified, including the genome-wide risk gene for psychiatric disorder CACNB2. First results of functional analyses in rat hippocampal neurons neither revealed nor excluded a major contribution of miR-499 or miR-708 to dendritic spine morphogenesis. The present results suggest that research is warranted to elucidate the precise involvement of microRNAs and their downstream pathways in BD.
61 citations
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TL;DR: Together, two novel factors that control neuronal miRISC function at the level of Ago proteins are uncovered, with possible implications for the regulation of synapse development and plasticity.
Abstract: MicroRNAs (miRNAs) are important regulators of neuronal development, network connectivity, and synaptic plasticity. While many neuronal miRNAs were previously shown to modulate neuronal morphogenesis, little is known regarding the regulation of miRNA function. In a large‐scale functional screen, we identified two novel regulators of neuronal miRNA function, Nova1 and Ncoa3. Both proteins are expressed in the nucleus and the cytoplasm of developing hippocampal neurons. We found that Nova1 and Ncoa3 stimulate miRNA function by different mechanisms that converge on Argonaute (Ago) proteins, core components of the miRNA‐induced silencing complex (miRISC). While Nova1 physically interacts with Ago proteins, Ncoa3 selectively promotes the expression of Ago2 at the transcriptional level. We further show that Ncoa3 regulates dendritic complexity and dendritic spine maturation of hippocampal neurons in a miRNA‐dependent fashion. Importantly, both the loss of miRNA activity and increased dendrite complexity upon Ncoa3 knockdown were rescued by Ago2 overexpression. Together, we uncovered two novel factors that control neuronal miRISC function at the level of Ago proteins, with possible implications for the regulation of synapse development and plasticity.
44 citations
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TL;DR: The emerging picture is an intricate crosstalk between different ncRNA families, mRNAs and RNA-binding proteins (RBPs) that synergistically fine-tune the local dendritic proteome in an activity-dependent manner.
31 citations
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TL;DR: A global decrease in microRNAs as common hallmark of different forms of amyotrophic lateral sclerosis (ALS) is reported and enhancing microRNA biogenesis has beneficial effects on the neuromuscular function in mouse models of ALS.
Abstract: MicroRNAs have emerged as crucial regulators of neuronal function, suggesting that aberrant microRNA expression might contribute to pathologies of the nervous system. In this issue of The EMBO Journal , Emde et al (2015) report a global decrease in microRNAs as common hallmark of different forms of amyotrophic lateral sclerosis (ALS). Strikingly, enhancing microRNA biogenesis has beneficial effects on the neuromuscular function in mouse models of ALS. Thus, the microRNA pathway represents a promising novel target for therapeutic intervention in neurodegeneration.
7 citations