Partanen Sanna, Haapanen Aleksi, Kielar Catherine, Pontikis Charles, Alexander Noreen, Inkinen Teija, Saftig Paul, Gillingwater Thomas H, Cooper Jonathan D, Tyynelä Jaana
Institute of Biomedicine/Biochemistry, University of Helsinki, Finland.
J Neuropathol Exp Neurol. 2008 Jan;67(1):16-29. doi: 10.1097/nen.0b013e31815f3899.
Cathepsin D (CTSD; EC 3.4.23.5) is a lysosomal aspartic protease, the deficiency of which causes early-onset and particularly aggressive forms of neuronal ceroid-lipofuscinosis in infants, sheep, and mice. Cathepsin D deficiencies are characterized by severe neurodegeneration, but the molecular mechanisms behind the neuronal death remain poorly understood. In this study, we have systematically mapped the distribution of neuropathologic changes in CTSD-deficient mouse brains by stereologic, immunologic, and electron microscopic methods. We report highly accentuated neuropathologic changes within the ventral posterior nucleus (ventral posteromedial [VPM]/ventral posterolateral [VPL]) of thalamus and in neuronal laminae IV and VI of the somatosensory cortex (S1BF), which receive and send information to the thalamic VPM/VPL. These changes included pronounced astrocytosis and microglial activation that begin in the VPM/VPL thalamic nucleus of CTSD-deficient mice and are associated with reduced neuronal number and redistribution of presynaptic markers. In addition, loss of synapses, axonal pathology, and aggregation of synaptophysin and synaptobrevin were observed in the VPM/VPL. These synaptic alterations are accompanied by changes in the amount of synaptophysin/synaptobrevin heterodimer, which regulates formation of the SNARE complex at the synapse. Taken together, these data reveal the somatosensory thalamocortical circuitry as a particular focus of pathologic changes and provide the first evidence for synaptic alterations at the molecular and ultrastructural levels in CTSD deficiency.
组织蛋白酶D（CTSD；EC 3.4.23.5）是一种溶酶体天冬氨酸蛋白酶，其缺乏会导致婴儿、绵羊和小鼠出现早发性且尤为侵袭性的神经元蜡样脂褐质沉积症。组织蛋白酶D缺乏症的特征是严重的神经退行性变，但神经元死亡背后的分子机制仍知之甚少。在本研究中，我们通过体视学、免疫学和电子显微镜方法系统地绘制了CTSD缺陷小鼠大脑中神经病理变化的分布图。我们报告了丘脑腹后核（腹后内侧[VPM]/腹后外侧[VPL]）以及躯体感觉皮层（S1BF）的IV层和VI层神经元中高度突出的神经病理变化，这些区域接收并向丘脑VPM/VPL发送信息。这些变化包括明显的星形细胞增生和小胶质细胞激活，始于CTSD缺陷小鼠的VPM/VPL丘脑核，并与神经元数量减少和突触前标记物的重新分布有关。此外，在VPM/VPL中观察到突触丧失、轴突病变以及突触素和突触囊泡蛋白的聚集。这些突触改变伴随着突触素/突触囊泡蛋白异二聚体数量的变化，该异二聚体调节突触处SNARE复合体的形成。综上所述，这些数据揭示了躯体感觉丘脑皮质回路是病理变化的一个特定焦点，并为CTSD缺乏症在分子和超微结构水平上的突触改变提供了首个证据。
