Microglial response promotes neurodegeneration in the Ndufs4 KO mouse model of Leigh syndrome

Abstract

Leigh syndrome is a mitochondrial disease characterized by neurodegeneration, neuroinflammation, and early death. Mice lacking NDUFS4, a mitochondrial complex I subunit (Ndufs4 KO mice), have been established as a good animal model for studying human pathology associated with Leigh syndrome. As the disease progresses, there is an increase in neurodegeneration and neuroinflammation, thereby leading to deteriorating neurological symptoms, including motor deficits, breathing alterations, and eventually, death of the animal. However, despite the magnitude of neuroinflammation associated with brain lesions, the role of neuroinflammatory pathways and their main cellular components have not been addressed directly as relevant players in the disease pathology. Here, we investigate the role of microglial cells, the main immune cells of the CNS, in Leigh-like syndrome pathology, by pharmacologically depleting them using the colony-stimulating factor 1 receptor antagonist PLX3397. Microglial depletion extended lifespan and delayed motor symptoms in Ndufs4 KO mice, likely by preventing neuronal loss. Next, we investigated the role of the major cytokine interleukin-6 (IL-6) in the disease progression. IL-6 deficiency partially rescued breathing abnormalities and modulated gliosis but did not extend the lifespan or rescue motor decline in Ndufs4 KO mice. The present results show that microglial accumulation is pathogenic, in a process independent of IL-6, and hints toward a contributing role of neuroinflammation in the disease of Ndufs4 KO mice and potentially in patients with Leigh syndrome.

Peripheral macrophages causally contribute to disease onset and progression in theNdufs4(KO) model of Leigh syndrome

“…The findings in this study are consistent with recent work by the Hidalgo laboratory, and our own prior work, demonstrating that low dose pexidartinib, used to eliminate microglia while sparing peripheral macrophages, only modestly alters disease course in the Ndufs4(KO) [1,24]. These data indicate that microglia contribute only partially to the pathogenesis of LS and that targeting microglia alone is insufficient to disrupt disease.…”

The immune system as a driver of mitochondrial disease pathogenesis: a review of evidence

“…CSF1R inhibition rescued disease, including both a complete prevention of CNS lesions and a rescue of peripheral symptoms such as metabolic dysfunction and cachexia [112]. Very recently, the partial benefits provided by low doses of PLX3397 have been independently reproduced by another group [116]. Together, these data provide strong evidence that LS is an immune-mediated disease.…”

Continuous Hypoxia Reduces Retinal Ganglion Cell Degeneration in a Mouse Model of Mitochondrial Optic Neuropathy

“…Along these lines, we should note that two recent studies reported that treatment of germline ndufs4 − / − mice with the colony stimulating factor-1 receptor (CSF1R) inhibitor pexidartinib resulted not only in depletion of Iba1 + mononuclear cells but also in suppression of brain lesion formation, reduction of neurological dysfunction, and prolongation of the lifespan of the mice. 39 , 68 These findings suggest that combatting inflammation can be neuroprotective in the setting of complex I dysfunction. Future studies in our mouse model testing whether the combination of anti-inflammatory interventions with hypoxia may result in additive or even synergistic RGC neuroprotection would therefore be very interesting.…”