Loss of Correlations among Proteins in Brains of the Ts65Dn Mouse Model of Down Syndrome

The Ts65Dn mouse model of Down syndrome (DS) is trisomic
for orthologs
of 88 of 161 classical protein coding genes present on human chromosome
21 (HSA21). Ts65Dn mice display learning and memory impairments and
neuroanatomical, electrophysiological, and cellular abnormalities
that are relevant to phenotypic features seen in DS; however, little
is known about the molecular perturbations underlying the abnormalities.
Here we have used reverse phase protein arrays to profile 64 proteins
in the cortex, hippocampus, and cerebellum of Ts65Dn mice and littermate
controls. Proteins were chosen to sample a variety of pathways and
processes and include orthologs of HSA21 proteins and phosphorylation-dependent
and -independent forms of non-HSA21 proteins. Protein profiles overall
show remarkable stability to the effects of trisomy, with fewer than
30% of proteins altered in any brain region. However, phospho-proteins
are less resistant to trisomy than their phospho-independent forms,
and Ts65Dn display abnormalities in some key proteins. Importantly,
we demonstrate that Ts65Dn mice have lost correlations seen in control
mice among levels of functionally related proteins, including components
of the MAP kinase pathway and subunits of the NMDA receptor. Loss
of normal patterns of correlations may compromise molecular responses
to stimulation and underlie deficits in learning and memory.

唐氏综合症（DS）的Ts65Dn小鼠模型对于人类染色体21（HSA21）上存在的161个经典蛋白质编码基因中的88个同源基因呈三倍体状态。Ts65Dn小鼠表现出学习和记忆障碍，以及与DS表型特征相关的神经解剖学、电生理学和细胞学异常；然而，关于这些异常背后的分子扰动知之甚少。在本研究中，我们利用反向蛋白芯片技术对Ts65Dn小鼠及其同窝小鼠的大脑皮层、海马体和小脑中的64种蛋白质进行了检测。所选择的蛋白质旨在采样多种途径和过程，包括HSA21蛋白的同源蛋白以及非HSA21蛋白的磷酸化依赖性和非依赖性形式。蛋白质谱总体上对三倍体效应表现出显著的稳定性，任何脑区中改变的蛋白质不到30%。然而，磷酸化蛋白相对于其非依赖性形式对三倍体的抵抗力较弱，Ts65Dn小鼠在某些关键蛋白中表现出异常。重要的是，我们证明了Ts65Dn小鼠在功能相关蛋白的水平上，包括MAP激酶途径的组分和NMDA受体的亚基，失去了与对照小鼠中观察到的相关性。正常相关模式的丧失可能损害对刺激的分子反应，并导致学习和记忆能力下降。