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.

Reduction of Synaptojanin 1 Accelerates Aβ Clearance and Attenuates Cognitive Deterioration in an Alzheimer Mouse Model

“…More importantly, increased synj1 expression has been functionally linked to the enlargement of early endosomes (46). It has been reported that endosome anomalies are the earliest specific pathology reported in AD brain tissue (47,48).…”

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

“…A reduction in the dose of the chromosome 21 gene cystatin B (CSTB), which encodes an endogenous inhibitor of lysosomal cathepsins, decreases the accumulation of Aβ and associated cognitive deficits 147 . Overexpression of another chromosome 21 gene, synaptojanin 1 (SYNJ1), which encodes a phosphoinositide phosphatase that regulates levels of membrane phosphatidylinositol-4,5-bisphosphate, has been associated with endosomal enlargement 148 , whereas reduced expression of SYNJ1 lowers Aβ accumulation, as well as neuronal dysfunction and cognitive deficits 149,150 . How endosomal enlargement caused by trisomy contributes to neuronal dysfunction and degeneration is another important area for future research.…”

“…For example, ubiquitin-specific peptidase 16 (USP16) or DYRK1A upregulation alters stem cell fate [167][168][169] , which may in turn alter neuronal differentiation. Additionally, overexpression of several chromosome 21 genes (for example, the microRNA gene mir-155 and the protein-coding genes SYNJ1, regulator of calcineurin 1 (RCAN1), intersectin 1 (ITSN1) and DS cell adhesion molecule (DSCAM)) has been implicated in deficits in synaptic structure and function 148,170,171 . These genes may also play a part in AD-DS, perhaps via an effect on APP processing or on cognitive reserve.…”

Allogeneic T cell responses are regulated by a specific miRNA-mRNA network

“…It has been associated with the development of neuronal diseases in mice and humans (30,53). Its role and expression in T cells has heretofore not been reported.…”