title: Trisomy for synaptojanin1 in Down syndrome is functionally linked to the enlargement of early endosomes.
abstract: 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.
authors.affiliation: Centre de Recherche de l’Institut du Cerveau et de la Moelle, CNRS UMR7225, UPMC, INSERM UMRS975, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Jack-Christophe
authors.initials: JC
authors.lastname: Cossec
authors.forename: Jérémie
authors.initials: J
authors.lastname: Lavaur
authors.forename: Diego E
authors.initials: DE
authors.lastname: Berman
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rivals
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.forename: Samantha
authors.initials: S
authors.lastname: Stora
authors.forename: Clémentine
authors.initials: C
authors.lastname: Ripoll
authors.forename: Clotilde
authors.initials: C
authors.lastname: Mircher
authors.forename: Yann
authors.initials: Y
authors.lastname: Grattau
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Olivomarin
authors.forename: Fabrice
authors.initials: F
authors.lastname: de Chaumont
authors.forename: Magalie
authors.initials: M
authors.lastname: Lecourtois
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.forename: Jean M
authors.initials: JM
authors.lastname: Delabar
authors.forename: Charles
authors.initials: C
authors.lastname: Duyckaerts
authors.forename: Gilbert
authors.initials: G
authors.lastname: Di Paolo
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Potier
mesh_terms: D000818:Animals; D002460:Cell Line; D002874:Chromosome Mapping; D002891:Chromosomes, Human, Pair 21 / Q000201:enzymology / Q000235:genetics; D004314:Down Syndrome / Q000201:enzymology* / Q000235:genetics; D011992:Endosomes / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism*; D014314:Trisomy
chemical_list: D009419:Nerve Tissue Proteins; C097702:synaptojanin; D010744:Phosphoric Monoester Hydrolases