Reim Dominik, Distler Ute, Halbedl Sonja, Verpelli Chiara, Sala Carlo, Bockmann Juergen, Tenzer Stefan, Boeckers Tobias M, Schmeisser Michael J
Institute for Anatomy and Cell Biology, Ulm UniversityUlm, Germany; International Graduate School in Molecular Medicine, Ulm UniversityUlm, Germany.
Institute for Immunology, University Medical Center of the Johannes-Gutenberg University MainzMainz, Germany; Focus Program Translational Neurosciences, University Medical Center of the Johannes-Gutenberg University MainzMainz, Germany.
Front Mol Neurosci. 2017 Feb 14;10:26. doi: 10.3389/fnmol.2017.00026. eCollection 2017.
Disruption of the human gene can cause several neuropsychiatric disease entities including Phelan-McDermid syndrome, autism spectrum disorder (ASD), and intellectual disability. Although, a wide array of neurobiological studies strongly supports a major role for SHANK3 in organizing the post-synaptic protein scaffold, the molecular processes at synapses of individuals harboring mutations are still far from being understood. In this study, we biochemically isolated the post-synaptic density (PSD) fraction from striatum and hippocampus of adult mutant mice and performed ion-mobility enhanced data-independent label-free LC-MS/MS to obtain the corresponding PSD proteomes (Data are available via ProteomeXchange with identifier PXD005192). This unbiased approach to identify molecular disturbances at mutant PSDs revealed hitherto unknown brain region specific alterations including a striatal decrease of several molecules encoded by ASD susceptibility genes such as the serine/threonine kinase Cdkl5 and the potassium channel K1.1. Being the first comprehensive analysis of brain region specific PSD proteomes from a mutant line, our study provides crucial information on molecular alterations that could foster translational treatment studies for mutation-associated synaptopathies and possibly also ASD in general.
人类基因的破坏可导致多种神经精神疾病，包括费兰 - 麦克德米德综合征、自闭症谱系障碍（ASD）和智力残疾。尽管大量神经生物学研究有力地支持了SHANK3在组织突触后蛋白支架中的主要作用，但携带突变个体突触处的分子过程仍远未被理解。在本研究中，我们从成年突变小鼠的纹状体和海马体中生物化学分离出突触后致密物（PSD）部分，并进行离子淌度增强的非数据依赖型无标记液相色谱 - 串联质谱分析，以获得相应的PSD蛋白质组（数据可通过ProteomeXchange获得，标识符为PXD005192）。这种识别突变型PSD分子干扰的无偏倚方法揭示了迄今未知的脑区特异性改变，包括由ASD易感基因编码的几种分子在纹状体中的减少，如丝氨酸/苏氨酸激酶Cdkl5和钾通道K1.1。作为对突变系脑区特异性PSD蛋白质组的首次全面分析，我们的研究提供了关于分子改变的关键信息，这可能有助于针对与突变相关的突触病变以及可能的一般ASD的转化治疗研究。
