Mice deficient for the chromosome 21 ortholog Itsn1 exhibit vesicle-trafficking abnormalities

Abstract

Enlarged early endosomes in the neurons of young Down syndrome (DS) and pre-Alzheimer's disease (AD) brains suggest that a disturbance in endocytosis is one of the earliest hallmarks of AD pathogenesis in both conditions. We identified a chromosome 21 gene, Intersectin-1 (ITSN1) that is up-regulated in DS brains and has a putative function in endocytosis and vesicle trafficking. To elucidate the function of ITSN1 and assess its contribution to endocytic defects associated with DS and AD, we generated Itsn1 null mice. In knockout mice we found alterations in a number of parameters associated with endocytic and vesicle trafficking events. We found a reduced number of exocytosis events in chromaffin cells and a slowing of endocytosis in neurons. Endosome size was increased in neurons and NGF levels were reduced in the septal region of the brain. Our data is the first indication that Itsn1 has a role in endocytosis in an in vivo mammalian model, and that a disruption in Itsn1 expression causes a disturbance in vesicle trafficking and endocytic function in the brain. These results imply a role for ITSN1 in the early endocytic anomalies reported in DS brains which may have ramifications for the onset of AD.

Upregulation of threeDrosophilahomologs of human chromosome 21 genes alters synaptic function: Implications for Down syndrome

“…Dap160 mutant flies also show perturbed synaptic vesicle recycling at the larval neuromuscular junctions (NMJ), implying that dap160 is involved in synaptic vesicle endocytosis (28,29). Similar conclusions were recently derived from studies using intersectin knockout mice, which exhibit defective endocytosis and enlarged endosomes (33). Furthermore, overexpression of intersectin in COS cells block receptor-mediated endocytosis (34), but the effect of its overexpression in synaptic vesicle endocytosis in neuronal cells at a more physiological range remains undetermined.…”

Fast neurotransmitter release regulated by the endocytic scaffold intersectin

“…To study the role of intersectin 1 in fast neurotransmission, we examined synaptic responses in intersectin 1 KO mice (20), in which expression of all isoforms of intersectin 1 is abrogated. Loss of intersectin 1 did not cause any overt differences in the morphological architecture or composition of the calyx or of the medial nucleus of the trapezoid body (MNTB) area in the brainstem.…”

“…Calyces from KO also showed no alterations in the localization or the amount of major endocytic proteins, such as clathrin and adaptor protein complex-2 (AP-2) (Fig. S2), arguing against major alterations or compensatory changes with respect to the endocytic machinery (20).…”

“…Although a role for intersectin in endocytosis has been established in Drosophila (16,17), the precise function of intersectin 1 in mammalian central synapses has not yet been analyzed extensively. Optical measurements of endocytosis in cultured neurons suggest mild effects on endocytosis as a consequence of intersectin 1 KO (20). These results indicate that intersectin might not be mandatory for SV membrane retrieval or might regulate other steps in endocytosis that are not rate-limiting for the process per se (21).…”

Intersectin 1: a molecular linker in the central nervous system

“…This strongly supported our hypothesis that intersectin 1-L functions in endocytosis and exocytosis. However, the distinct role of intersectin 1-S still needs further research and investigation to reveal its functions [27] . …”