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

被引:78
作者
Cossec, Jack-Christophe [1 ]
Lavaur, Jeremie [1 ]
Berman, Diego E. [2 ,3 ]
Rivals, Isabelle [4 ]
Hoischen, Alexander [5 ]
Stora, Samantha [6 ]
Ripoll, Clementine [7 ]
Mircher, Clotilde [6 ]
Grattau, Yann [6 ]
OlivoMarin, Jean-Christophe [8 ]
de Chaumont, Fabrice [8 ]
Lecourtois, Magalie [9 ]
Antonarakis, Stylianos E. [10 ]
Veltman, Joris A. [5 ]
Delabar, Jean M. [7 ]
Duyckaerts, Charles [1 ]
Di Paolo, Gilbert [2 ,3 ]
Potier, Marie-Claude [1 ]
机构
[1] Hop La Pitie Salpetriere, CNRS UMR7225, INSERM UMRS975, Inst Cerveau & Moelle,Ctr Rech,UPMC, F-75013 Paris, France
[2] Columbia Univ, Med Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA
[3] Columbia Univ, Med Ctr, Dept Pathol & Cell Biol, New York, NY USA
[4] ESPCI ParisTech, Equipe Stat Appl, Paris, France
[5] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands
[6] Inst Jerome Lejeune, Paris, France
[7] Univ Paris Diderot, Unite Biol Fonct & Adaptat BFA CNRS EAC4413, Paris, France
[8] Inst Pasteur, Quantitat Image Anal Unit, CNRS URA2582, Paris, France
[9] INSERM U 614, Rouen, France
[10] Univ Geneva, Geneva, Switzerland
基金
美国国家卫生研究院;
关键词
SPORADIC ALZHEIMERS-DISEASE; GENE; EXPRESSION; MOUSE; ENDOCYTOSIS; PHOSPHORYLATION; TRAFFICKING; CLATHRIN; BRAIN; CHROMOSOME-21;
D O I
10.1093/hmg/dds142
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 Alzheimers 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. Genotypephenotype 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.
引用
收藏
页码:3156 / 3172
页数:17
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