Genetic diversity of axon degenerative mechanisms in models of Parkinson's disease.
Genetic diversity of axon degenerative mechanisms in models of Parkinson's disease.
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DOI：
10.1016/j.nbd.2021.105368
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发表时间：
2021-07
影响因子：
6.1
通讯作者：
Freeman M
中科院分区：
文献类型：
--
作者：
Peters OM;Weiss A;Metterville J;Song L;Logan R;Smith GA;Schwarzschild MA;Mueller C;Brown RH;Freeman M
帕金森病（PD）是最常见的神经退行性运动障碍形式，与基底神经节多巴胺能神经元的严重损失相关。虽然多巴胺能神经元胞体从黑质部的损失是一个充分研究的特点，萎缩和黑质纹状体内的轴突损失也出现作为疾病进展的早期事件。驱动Wallerian变性的基因，如Sterile alpha和toll/白细胞介素-1受体基序（Sarm 1），是驱动这种轴突变性的极好候选者，因为轴突切断后轴突变性的形态与PD相似。在本研究中，我们评估了Sarm 1是否有助于PD小鼠模型中多巴胺能投射的丧失。在SARM 1缺陷小鼠中，我们观察到在黑质纹状体束内侧前脑束（MFB）的6-OHDA病变远端的切断多巴胺能轴突的变性显著延迟，以及伴随的形态学、生化和行为表型的拯救。然而，当用6-OHDA损伤纹状体末端以诱导神经变性的死亡形式时，我们观察到与对照组相比没有差异。同样，当使用AAV诱导的α-突触核蛋白过表达诱导PD表型时，我们在Sarm 1敲除和对照中观察到类似的多巴胺能末梢的适度损失。我们的数据表明，MFB损伤后的轴突变性是Sarm 1依赖性的，但其他PD模型不需要Sarm 1，或者Sarm 1与其他冗余的遗传途径一起起作用。这项工作增加了越来越多的证据表明Sarm 1有助于一些，但不是所有类型的神经变性，并支持这样的观点，即虽然轴突变性在许多情况下在形态上相似，但存在多种轴突变性程序。
Parkinson’s disease (PD) is the most common form of neurodegenerative movement disorder, associated with profound loss of dopaminergic neurons from the basal ganglia. Though loss of dopaminergic neuron cell bodies from the substantia nigra pars compacta is a well-studied feature, atrophy and loss of their axons within the nigrostriatal tract is also emerging as an early event in disease progression. Genes that drive the Wallerian degeneration, like Sterile alpha and toll/interleukin-1 receptor motif containing (Sarm1), are excellent candidates for driving this axon degeneration, given similarities in the morphology of axon degeneration after axotomy and in PD. In the present study we assessed whether Sarm1 contributes to loss of dopaminergic projections in mouse models of PD. In Sarm1 deficient mice, we observed a significant delay in the degeneration of severed dopaminergic axons distal to a 6-OHDA lesion of the medial forebrain bundle (MFB) in the nigrostriatal tract, and an accompanying rescue of morphological, biochemical and behavioural phenotypes. However, we observed no difference compared to controls when striatal terminals were lesioned with 6-OHDA to induce a dying back form of neurodegeneration. Likewise, when PD phenotypes were induced using AAV-induced alpha-synuclein overexpression, we observed similar modest loss of dopaminergic terminals in Sarm1 knockouts and controls. Our data argues that axon degeneration after MFB lesion is Sarm1-dependent, but that other models for PD do not require Sarm1, or that Sarm1 acts with other redundant genetic pathways. This work adds to a growing body of evidence indicating Sarm1 contributes to some, but not all types of neurodegeneration, and supports the notion that while axon degeneration in many context appears morphologically similar, a diversity of axon degeneration programs exist.
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