Human Molecular Genetics Advance Access published online on August 2, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn224
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Mice deficient for the chromosome 21 ortholog Itsn1 exhibit vesicle trafficking abnormalities
1 Depts. Biochemistry & Molecular Biology and Anatomy & Developmental Biology, Monash University, Clayton, 3168, Victoria, Australia 2 The Howard Florey Institute, University of Melbourne, Parkville, 3052, Victoria, Australia 3 Molecular and Cellular Neuroscience Group, Department of Human Physiology and Centre for Neuroscience, Flinders University, 5042, Adelaide, Australia 4 Monash Micro Imaging, Monash University, Clayton, 3168, Victoria, Australia 5 Mental Health Research Institute of Victoria, Parkville, 3052, Victoria, Australia
* Corresponding author: Dr. Melanie Pritchard, Depts. Biochemistry & Molecular Biology and Anatomy & Developmental Biology, Monash University, Building 13C, Wellington Rd, Clayton, VIC 3800, Australia, Phone: +61 3 9905 2715, Fax: +61 3 9905 2462, Email: melanie.pritchard{at}med.monash.edu.au
Received May 11, 2008; Revised July 30, 2008; Accepted July 31, 2008
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 endocyic 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.
6 DIF and MAP are co-senior authors
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