Trisomy for Synaptojanin1 in Down syndrome is functionally linked to the enlargement of early endosomes

• Published in: Human molecular genetics Vol. 21; no. 14; pp. 3156 - 3172
• Main Authors: Cossec, Jack-Christophe, Lavaur, Jérémie, Berman, Diego E., Rivals, Isabelle, Hoischen, Alexander, Stora, Samantha, Ripoll, Clémentine, Mircher, Clotilde, Grattau, Yann, OlivoMarin, Jean-Christophe, de Chaumont, Fabrice, Lecourtois, Magalie, Antonarakis, Stylianos E., Veltman, Joris A., Delabar, Jean M., Duyckaerts, Charles, Di Paolo, Gilbert, Potier, Marie-Claude
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 15.07.2012; Oxford University Press (OUP)
• Subjects: Age; Alzheimer's disease; Amyloid precursor protein; Animals; Biological and medical sciences; Cell Line; chromosome 21; Chromosome aberrations; Chromosome Mapping; Chromosomes, Human, Pair 21 - enzymology; Chromosomes, Human, Pair 21 - genetics; Confocal microscopy; Down Syndrome - enzymology; Down Syndrome - genetics; Down's syndrome; Endocytosis; endosomes; Endosomes - chemistry; Endosomes - metabolism; Fibroblasts; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Humans; Immunofluorescence; Leukocytes (mononuclear); Life Sciences; Lymphoblastoid cell lines; Medical genetics; Medical sciences; Mice; Mice, Transgenic; Molecular and cellular biology; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neuroblastoma cells; Neurodegenerative diseases; Neurons and Cognition; phosphoinositides; Phospholipids; Phosphoric Monoester Hydrolases - genetics; Phosphoric Monoester Hydrolases - metabolism; RNA-mediated interference; Transgenic mice; Trisomy; Chromosomal aberration; Trisomy; Chromosome G21; Aneuploidy; Genetics; Early; Down syndrome; Endosome; endosomes; fibroblasts; down syndrome; trisomy; protein overexpression; neurons
• DOI: 10.1093/hmg/dds142
• ISSN: 0964-6906; 1460-2083

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.