Van Schoor E, Koper M J, Ospitalieri S, Dedeene L, Tomé S O, Vandenberghe R, Brenner D, Otto M, Weishaupt J, Ludolph A C, Van Damme P, Van Den Bosch L, Thal D R
Laboratory of Neuropathology, Department of Imaging and Pathology, KU Leuven (University of Leuven), Leuven Brain Institute (LBI), Leuven, Belgium.
Laboratory of Neurobiology, Department of Neurosciences, KU Leuven (University of Leuven), Leuven Brain Institute (LBI), Leuven, Belgium.
Neuropathol Appl Neurobiol. 2021 Feb;47(2):328-345. doi: 10.1111/nan.12668. Epub 2020 Oct 20.
Granulovacuolar degeneration (GVD) in Alzheimer's disease (AD) involves the necrosome, which is a protein complex consisting of phosphorylated receptor-interacting protein kinase 1 (pRIPK1), pRIPK3 and phosphorylated mixed lineage kinase domain-like protein (pMLKL). Necrosome-positive GVD was associated with neuron loss in AD. GVD was recently linked to the C9ORF72 mutation in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with transactive response DNA-binding protein (TDP-43) pathology (FTLD-TDP). Therefore, we investigated whether GVD in cases of the ALS-FTLD-TDP spectrum (ALS/FTLD) shows a similar involvement of the necrosome as in AD, and whether it correlates with diagnosis, presence of protein aggregates and cell death in ALS/FTLD.
We analysed the presence and distribution of the necrosome in post-mortem brain and spinal cord of ALS and FTLD-TDP patients (n = 30) with and without the C9ORF72 mutation, and controls (n = 22). We investigated the association of the necrosome with diagnosis, the presence of pathological protein aggregates and neuronal loss.
Necrosome-positive GVD was primarily observed in hippocampal regions of ALS/FTLD cases and was associated with hippocampal TDP-43 inclusions as the main predictor of the pMLKL-GVD stage, as well as with the Braak stage of neurofibrillary tangle pathology. The central cortex and spinal cord, showing motor neuron loss in ALS, were devoid of any accumulation of pRIPK1, pRIPK3 or pMLKL.
Our findings suggest a role for hippocampal TDP-43 pathology as a contributor to necrosome-positive GVD in ALS/FTLD. The absence of necroptosis-related proteins in motor neurons in ALS argues against a role for necroptosis in ALS-related motor neuron death.
阿尔茨海默病（AD）中的颗粒空泡变性（GVD）涉及坏死小体，它是一种由磷酸化的受体相互作用蛋白激酶1（pRIPK1）、pRIPK3和磷酸化的混合谱系激酶结构域样蛋白（pMLKL）组成的蛋白质复合物。坏死小体阳性的GVD与AD中的神经元丢失有关。最近，GVD与肌萎缩侧索硬化症（ALS）和具有反式激活反应DNA结合蛋白（TDP-43）病理改变的额颞叶痴呆（FTLD-TDP）中的C9ORF72突变有关。因此，我们研究了ALS-FTLD-TDP谱系（ALS/FTLD）病例中的GVD是否显示出与AD中类似的坏死小体参与情况，以及它是否与ALS/FTLD的诊断、蛋白聚集体的存在和细胞死亡相关。
我们分析了有和没有C9ORF72突变的ALS和FTLD-TDP患者（n = 30）以及对照（n = 22）的死后脑和脊髓中坏死小体的存在和分布。我们研究了坏死小体与诊断、病理性蛋白聚集体的存在和神经元丢失之间的关联。
坏死小体阳性的GVD主要在ALS/FTLD病例的海马区域观察到，并且与海马TDP-43包涵体相关，海马TDP-43包涵体是pMLKL-GVD阶段的主要预测指标，还与神经原纤维缠结病理的Braak阶段相关。在ALS中显示运动神经元丢失的中央皮质和脊髓没有pRIPK1、pRIPK3或pMLKL的任何积聚。
我们的研究结果表明海马TDP-43病理在ALS/FTLD中坏死小体阳性GVD的形成中起作用。ALS运动神经元中缺乏坏死性凋亡相关蛋白表明坏死性凋亡在ALS相关运动神经元死亡中不起作用。
