Mechanisms of Compartmental Purkinje Cell Death and Survival in the Lurcher Mutant Mouse
Mechanisms of Compartmental Purkinje Cell Death and Survival in the Lurcher Mutant Mouse
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DOI：
10.1007/s12311-010-0231-4
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发表时间：
2011-09-01
期刊：
影响因子：
3.5
通讯作者：
Vogel, Michael William
中科院分区：
文献类型：
--
作者：
Armstrong, Carol L.;Duffin, Catherine A.;Vogel, Michael William
Lurcher突变小鼠的特征是步态不同，在出生后第一周的发育过程中，小脑浦肯野细胞及其传入细胞、颗粒细胞和橄榄核神经元丢失。自发现以来的50年里，杂合子Lurcher突变体一直是研究发育中的小脑和小脑功能中神经元与靶点相互作用的重要模型系统。早在10多年前，Lurcher(LC)基因被鉴定为Delta 2谷氨酸受体(GluR Delta 2)的功能获得突变，导致了对LC/+小脑细胞死亡机制的广泛研究。这个模型系统的优点是Glur delta2(+)受体和Glur delta2(LC)通道主要在Purkinje细胞中表达，这使得在神经元发育的关键阶段研究明确定义的细胞类型中明确描述的泄漏电流的影响成为可能。然而，由于Glu R delta2(LC)泄漏电流引起的兴奋性毒性应激，关于LC/+Purkinje细胞中神经元死亡的机制仍存在争议，对坏死、凋亡和自噬细胞死亡途径的假说相互竞争。这篇综述的目的是总结最近的研究，这些研究针对浦肯野细胞分子异质性的证据，关键地测试了各种细胞死亡途径在LC/+浦肯野细胞退变中的作用。我们认为，可能的生存因子，如热休克蛋白，在小脑浦肯野细胞亚群中的表达可能影响细胞死亡途径，并解释LC/+浦肯野变性的模式和不同的机制。
The Lurcher mutant mouse is characterized by its ataxic gait and loss of cerebellar Purkinje cells and their afferents, granule cells and olivary neurons, during the first weeks of postnatal development. For the 50 years since its discovery, the heterozygous Lurcher mutant has served as an important model system for studying neuron-target interactions in the developing cerebellum and cerebellar function. The identification of the Lurcher (Lc) gene over 10 years ago as a gain-of-function mutation in the delta 2 glutamate receptor (GluR delta 2) led to extensive studies of cell death mechanisms in the Lc/+ cerebellum. The advantage of this model system is that GluR delta 2(+) receptors and GluR delta 2 (Lc) channels are expressed predominantly in Purkinje cells, making it possible to study the effects of a well-characterized leak current in a well-defined cell type during a critical phase of neuronal development. Yet there is still controversy surrounding the mechanisms of neuronal death in Lc/+ Purkinje cells with competing hypotheses for necrotic, apoptotic, and autophagic cell death pathways as a consequence of the excitotoxic stress caused by the GluR delta 2 (Lc) leak current. The goal of this review is to summarize recent studies that critically test the role of various cell death pathways in Lc/+ Purkinje cell degeneration with respect to evidence for the molecular heterogeneity of Purkinje cells. We propose that the expression of putative survival factors, such as heat shock proteins, in a subset of cerebellar Purkinje cells may affect cell death pathways and account for the pattern and diverse mechanisms of Lc/+ Purkinje degeneration.