Disposition of Proteins and Lipids in Synaptic Membrane Compartments Is Altered in Q175/Q7 Huntington's Disease Mouse Striatum.
Disposition of Proteins and Lipids in Synaptic Membrane Compartments Is Altered in Q175/Q7 Huntington's Disease Mouse Striatum.
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DOI：
10.3389/fnsyn.2021.618391
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发表时间：
2021
影响因子：
3.7
通讯作者：
Kegel-Gleason KB
中科院分区：
文献类型：
--
作者：
Iuliano M;Seeley C;Sapp E;Jones EL;Martin C;Li X;DiFiglia M;Kegel-Gleason KB
突触功能障碍被认为是导致亨廷顿病（HD）认知、精神和运动障碍的早期变化。在神经元中，突变的亨廷顿蛋白聚集在聚集体中，并分布到与野生型亨廷顿蛋白相同的位点，包括膜上和突触中。在这项研究中，我们调查了生化完整性突触在HD小鼠纹状体。我们对2和6个月大的敲入Q175/Q7 HD和Q7/Q7小鼠的纹状体组织进行了亚细胞分级分离。与Q7/Q7小鼠的纹状体相比，包括GLUT 3、Na+/K+ ATP酶、NMDAR 2b、PSD 95和VGLUT 1在内的蛋白质在6月龄小鼠的Q175/Q7 HD纹状体中的分布发生了改变，但在2月龄小鼠的纹状体中没有改变。这些蛋白质存在于质膜和突触前膜和突触后膜上，支持突触功能变化导致HD认知和行为症状的假设。小鼠级分的脂质组学分析表明，与野生型相比，6个月Q175/Q7 HD的级分1和2具有改变的两种PIP 2（参与突触信号传导的磷脂）水平、增加的胆固醇酯水平和减少的心磷脂种类。在2个月时，测量到酰基肉毒碱、磷脂酸和鞘磷脂的种类水平增加。电镜分析表明，Q7/Q7和Q175/Q7 HD纹状体组分1和组分2的内容物具有分离的突触小泡、单个或成簇的充满轴突终末的小泡以及ER和内体样膜的混合物。然而，与Q7/Q7相比，Q175/Q7 striata的那些包含显著更少和更大的颗粒团块。人HD死后壳核中两种蛋白质（Calnexin和GLUT 3）的亚细胞分布与对照壳核存在差异。我们的生物化学、脂质组学和EM分析表明，HD突变的存在赋予了对突触功能重要的突触蛋白和脂质的定位的年龄依赖性破坏。我们的数据表明，具体的生化变化表明，在HD小鼠的突触室的完整性，可能反映在HD患者的变化，并预示着认知和精神的变化，发生在表现前HD改变。
Dysfunction at synapses is thought to be an early change contributing to cognitive, psychiatric and motor disturbances in Huntington’s disease (HD). In neurons, mutant Huntingtin collects in aggregates and distributes to the same sites as wild-type Huntingtin including on membranes and in synapses. In this study, we investigated the biochemical integrity of synapses in HD mouse striatum. We performed subcellular fractionation of striatal tissue from 2 and 6-month old knock-in Q175/Q7 HD and Q7/Q7 mice. Compared to striata of Q7/Q7 mice, proteins including GLUT3, Na+/K+ ATPase, NMDAR 2b, PSD95, and VGLUT1 had altered distribution in Q175/Q7 HD striata of 6-month old mice but not 2-month old mice. These proteins are found on plasma membranes and pre- and postsynaptic membranes supporting hypotheses that functional changes at synapses contribute to cognitive and behavioral symptoms of HD. Lipidomic analysis of mouse fractions indicated that compared to those of wild-type, fractions 1 and 2 of 6 months Q175/Q7 HD had altered levels of two species of PIP2, a phospholipid involved in synaptic signaling, increased levels of cholesterol ester and decreased cardiolipin species. At 2 months, increased levels of species of acylcarnitine, phosphatidic acid and sphingomyelin were measured. EM analysis showed that the contents of fractions 1 and 2 of Q7/Q7 and Q175/Q7 HD striata had a mix of isolated synaptic vesicles, vesicle filled axon terminals singly or in clusters, and ER and endosome-like membranes. However, those of Q175/Q7 striata contained significantly fewer and larger clumps of particles compared to those of Q7/Q7. Human HD postmortem putamen showed differences from control putamen in subcellular distribution of two proteins (Calnexin and GLUT3). Our biochemical, lipidomic and EM analysis show that the presence of the HD mutation conferred age dependent disruption of localization of synaptic proteins and lipids important for synaptic function. Our data demonstrate concrete biochemical changes suggesting altered integrity of synaptic compartments in HD mice that may mirror changes in HD patients and presage cognitive and psychiatric changes that occur in premanifest HD.
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影响因子：
4.8
作者：
de Chaves, EIP;Rusiñol, AE;Vance, JE
通讯作者：
Vance, JE
影响因子：
5.5
作者：
Dason, Jeffrey S.;Smith, Alex J.;Charlton, Milton P.
通讯作者：
Charlton, Milton P.
影响因子：
16.2
作者：
DIFIGLIA, M;SAPP, E;ARONIN, N
通讯作者：
ARONIN, N
影响因子：
5.3
作者：
Dason, Jeffrey S.;Smith, Alex J.;Charlton, Milton P.
通讯作者：
Charlton, Milton P.
影响因子：
3.5
作者：
Choo, YS;Johnson, GVW;Lesort, M
通讯作者：
Lesort, M