Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Nat Neurosci. 2019 Oct;22(10):1635-1648. doi: 10.1038/s41593-019-0486-0. Epub 2019 Sep 23.
In neurodegenerative diseases, debris of dead neurons are thought to trigger glia-mediated neuroinflammation, thus increasing neuronal death. Here we show that the expression of neurotoxic proteins associated with these diseases in microglia alone is sufficient to directly trigger death of naive neurons and to propagate neuronal death through activation of naive astrocytes to the A1 state. Injury propagation is mediated, in great part, by the release of fragmented and dysfunctional microglial mitochondria into the neuronal milieu. The amount of damaged mitochondria released from microglia relative to functional mitochondria and the consequent neuronal injury are determined by Fis1-mediated mitochondrial fragmentation within the glial cells. The propagation of the inflammatory response and neuronal cell death by extracellular dysfunctional mitochondria suggests a potential new intervention for neurodegeneration-one that inhibits mitochondrial fragmentation in microglia, thus inhibiting the release of dysfunctional mitochondria into the extracellular milieu of the brain, without affecting the release of healthy neuroprotective mitochondria.
在神经退行性疾病中，人们认为死亡神经元的残骸会引发神经胶质介导的神经炎症，从而增加神经元死亡。在这里，我们表明，仅在小胶质细胞中表达与这些疾病相关的神经毒性蛋白就足以直接引发未成熟神经元的死亡，并通过激活未成熟星形胶质细胞至 A1 状态来传播神经元死亡。损伤的传播在很大程度上是由破碎和功能失调的小胶质细胞线粒体释放到神经元环境中介导的。从小胶质细胞释放的受损线粒体相对于功能线粒体的数量以及由此导致的神经元损伤，是由胶质细胞内 Fis1 介导的线粒体片段化决定的。细胞外功能失调线粒体引发的炎症反应和神经元细胞死亡的传播表明，神经退行性变的一种潜在新干预措施——抑制小胶质细胞中线粒体的片段化，从而抑制功能失调的线粒体释放到大脑的细胞外环境中，而不影响健康的神经保护线粒体的释放。
