Document Detail

Trisomy for synaptojanin1 in Down syndrome is functionally linked to the enlargement of early endosomes.
MedLine Citation:
PMID:  22511594     Owner:  NLM     Status:  MEDLINE    
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.
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:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-04-17
Journal Detail:
Title:  Human molecular genetics     Volume:  21     ISSN:  1460-2083     ISO Abbreviation:  Hum. Mol. Genet.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-06-28     Completed Date:  2013-01-14     Revised Date:  2013-07-17    
Medline Journal Info:
Nlm Unique ID:  9208958     Medline TA:  Hum Mol Genet     Country:  England    
Other Details:
Languages:  eng     Pagination:  3156-72     Citation Subset:  IM    
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
Cell Line
Chromosome Mapping
Chromosomes, Human, Pair 21 / enzymology,  genetics
Down Syndrome / enzymology*,  genetics
Endosomes / chemistry*,  metabolism
Mice, Transgenic
Nerve Tissue Proteins / genetics*,  metabolism*
Phosphoric Monoester Hydrolases / genetics*,  metabolism*
Grant Support
Reg. No./Substance:
0/Nerve Tissue Proteins; EC 3.1.3.-/Phosphoric Monoester Hydrolases; EC 3.1.3.-/synaptojanin

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