Yu Yong, Chu Po-Yin, Bowser David N, Keating Damien J, Dubach Daphne, Harper Ian, Tkalcevic Josephine, Finkelstein David I, Pritchard Melanie A
Departments of Biochemistry and Molecular Biology and Anatomy and Developmental Biology, Monash University, Building 13C, Wellington Rd, Clayton 3168, Victoria, Australia.
Hum Mol Genet. 2008 Nov 1;17(21):3281-90. doi: 10.1093/hmg/ddn224. Epub 2008 Aug 2.
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.
在年轻的唐氏综合征（DS）和阿尔茨海默病（AD）前期大脑的神经元中，早期内体增大，这表明内吞作用紊乱是这两种病症中AD发病机制的最早标志之一。我们鉴定出一个21号染色体基因，即交叉蛋白-1（ITSN1），它在DS大脑中上调，并且在内吞作用和囊泡运输中具有假定功能。为了阐明ITSN1的功能并评估其对与DS和AD相关的内吞缺陷的影响，我们培育了It sn1基因敲除小鼠。在基因敲除小鼠中，我们发现了许多与内吞和囊泡运输事件相关的参数发生了改变。我们发现嗜铬细胞中的胞吐事件数量减少，神经元中的内吞作用减慢。神经元中的内体大小增加，大脑隔区的神经生长因子（NGF）水平降低。我们的数据首次表明，It sn1在体内哺乳动物模型的内吞作用中发挥作用，并且It sn1表达的破坏会导致大脑中囊泡运输和内吞功能紊乱。这些结果暗示ITSN1在DS大脑中报道的早期内吞异常中起作用，这可能对AD的发病有影响。
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