Mice deficient for the chromosome 21 ortholog Itsn1 exhibit vesicle-trafficking abnormalities.
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.
Yu
Yong
Y
Departments of Biochemistry and Molecular Biology and Anatomy and Developmental Biology, Monash University, Building 13C, Wellington Rd, Clayton 3168, Victoria, Australia.
Chu
Po-Yin
PY
Bowser
David N
DN
Keating
Damien J
DJ
Dubach
Daphne
D
Harper
Ian
I
Tkalcevic
Josephine
J
Finkelstein
David I
DI
Pritchard
Melanie A
MA
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D019439:Chromaffin Cells / Q000378:metabolism; D033481:Chromosomes, Mammalian / Q000235:genetics*; D005089:Exocytosis / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020932:Nerve Growth Factor / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D020033:Protein Isoforms; D013572:Synaptic Vesicles / Q000378:metabolism
D033942:Adaptor Proteins, Vesicular Transport; D020033:Protein Isoforms; C115919:intersectin 1; D020932:Nerve Growth Factor