| Trisomy for synaptojanin1 in Down syndrome is functionally linked to the enlargement of early endosomes. | |
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MedLine Citation:
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PMID: 22511594 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Enlarged early endosomes have been observed in neurons and fibroblasts in Down syndrome (DS). These endosome abnormalities have been implicated in the early development of Alzheimer's disease (AD) pathology in these subjects. Here, we show the presence of enlarged endosomes in blood mononuclear cells and lymphoblastoid cell lines (LCLs) from individuals with DS using immunofluorescence and confocal microscopy. Genotype-phenotype correlations in LCLs carrying partial trisomies 21 revealed that triplication of a 2.56 Mb locus in 21q22.11 is associated with the endosomal abnormalities. This locus contains the gene encoding the phosphoinositide phosphatase synaptojanin 1 (SYNJ1), a key regulator of the signalling phospholipid phosphatidylinositol-4,5-biphosphate that has been shown to regulate clathrin-mediated endocytosis. We found that SYNJ1 transcripts are increased in LCLs from individuals with DS and that overexpression of SYNJ1 in a neuroblastoma cell line as well as in transgenic mice leads to enlarged endosomes. Moreover, the proportion of enlarged endosomes in fibroblasts from an individual with DS was reduced after silencing SYNJ1 expression with RNA interference. In LCLs carrying amyloid precursor protein (APP) microduplications causing autosomal dominant early-onset AD, enlarged endosomes were absent, suggesting that APP overexpression alone is not involved in the modification of early endosomes in this cell type. These findings provide new insights into the contribution of SYNJ1 overexpression to the endosomal changes observed in DS and suggest an attractive new target for rescuing endocytic dysfunction and lipid metabolism in DS and in AD. |
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Authors:
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Jack-Christophe Cossec; Jérémie Lavaur; Diego E Berman; Isabelle Rivals; Alexander Hoischen; Samantha Stora; Clémentine Ripoll; Clotilde Mircher; Yann Grattau; Jean-Christophe Olivomarin; Fabrice de Chaumont; Magalie Lecourtois; Stylianos E Antonarakis; Joris A Veltman; Jean M Delabar; Charles Duyckaerts; Gilbert Di Paolo; Marie-Claude Potier |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-04-17 |
Journal Detail:
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Title: Human molecular genetics Volume: 21 ISSN: 1460-2083 ISO Abbreviation: Hum. Mol. Genet. Publication Date: 2012 Jul |
Date Detail:
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Created Date: 2012-06-28 Completed Date: 2013-01-14 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 9208958 Medline TA: Hum Mol Genet Country: England |
Other Details:
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Languages: eng Pagination: 3156-72 Citation Subset: IM |
Affiliation:
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Centre de Recherche de l’Institut du Cerveau et de la Moelle, CNRS UMR7225, UPMC, INSERM UMRS975, Hôpital Pitié-Salpêtrière, Paris, France. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Line Chromosome Mapping Chromosomes, Human, Pair 21 / enzymology, genetics Down Syndrome / enzymology*, genetics Endosomes / chemistry*, metabolism Humans Mice Mice, Transgenic Nerve Tissue Proteins / genetics*, metabolism* Phosphoric Monoester Hydrolases / genetics*, metabolism* Trisomy* |
| Grant Support | |
ID/Acronym/Agency:
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R01 HD055457/HD/NICHD NIH HHS; R01 HD055457/HD/NICHD NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Nerve Tissue Proteins; EC 3.1.3.-/Phosphoric Monoester Hydrolases; EC 3.1.3.-/synaptojanin |
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