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Developmental regulation of neuronal gene expression by Elongator complex protein 1 dosage

Journal of Genetics and Genomics 2022年第7期49卷 654-665页

作者： Elisabetta Morini Dadi Gao Emily M.Logan Monica Salani Aram J.Krauson Anil Chekuri Yei-Tsung Chen Ashok Ragavendran Probir Chakravarty Serkan Erdin Alexei Stortchevoi Jesper Q.Svejstrup Michael E.Talkowski Susan A.Slaugenhaupt Center for Genomic Medicine Massachusetts General Hospital Research InstituteBostonMAUSA Department of Neurology Massachusetts General Hospital Research Institute and Harvard Medical SchoolBostonMAUSA Program in Medical and Population Genetics and Stanley Center for Psychiatric Research Broad Institute of Harvard and MITCambridgeMAUSA Department of Life Sciences and Institute of Genome Sciences National Yang Ming Chiao Tung UniversityTaiwanChina Bioinformatics and Biostatistics The Francis Crick InstituteLondonUK Mechanisms of Transcription Laboratory The Francis Crick InstituteLondonUK Department of Cellular and Molecular Medicine Panum InstituteUniversity of CopenhagenCopenhagenDenmark

familial dysautonomia(FD), a hereditary sensory and autonomic neuropathy, is caused by a mutation in the Elongator complex protein 1(ELP1) gene that leads to a tissue-specific reduction of ELP1 protein. Our work to generate a phenotypic mouse model for FD headed to the discovery that homozygous deletion of the mouse Elp1 gene leads to embryonic lethality prior to mid-gestation. Given that FD is caused by a reduction, not loss, of ELP1, we generated two new mouse models by introducing different copy numbers of the human FD ELP1 transgene into the Elp1 knockout mouse(Elp1) and observed that human ELP1 expression rescues embryonic development in a dose-dependent manner. We then conducted a comprehensive transcriptome analysis in mouse embryos to identify genes and pathways whose expression correlates with the amount of ELP1. We found that ELP1 is essential for the expression of genes responsible for nervous system development. Further, gene length analysis of the differentially expressed genes showed that the loss of Elp1 mainly impacts the expression of long genes and that by gradually restoring Elongator, their expression is progressively rescued. Finally, through evaluation of co-expression modules, we identified gene sets with unique expression patterns that depended on ELP1 expression.

关键词： ELP1 Elongator Transcriptional elongation familial dysautonomia Neurodevelopmental disease

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Phosphatidylserine improves axonal transport by inhibition of HDAC and has potential in treatment of neurodegenerative diseases

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Neural Regeneration Research 2017年第4期12卷 534-537页

作者： Shiran Naftelberg Gil Ast Eran Perlson Department of Human Molecular Genetics and Biochemistry Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel Department of Physiology and Pharmacology Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel

familial dysautonomia （FD） is a rare children neurodegenerative disease caused due to a point mutation in the IKBKAP gene that results in decreased IKK complex-associated protein （IKAP） protein production. The disease affects mostly the dorsal root ganglion （DRG） and the sympathetic ganglion. Recently, we found that the molecular mechanisms underlying neurodegeneration in FD patients are defects in axonal transport of nerve growth factors and microtubule stability in the DRG. Neurons are highly polarized cells with very long axons. In order to survive and maintain proper function, neurons depend on transport of proteins and other cellular components from the neuronal body along the axons. We further demonstrated that IKAP is necessary for axon maintenance and showed that phosphatidylserine acts as an HDAC6 inhib- itor to rescue neuronal function in FD cells. In this review, we will highlight our latest research findings.

关键词： axonaI transport neurodegeneration microtubule familial dysautonomia phosphatidylserine HDAC6

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