Leukocytes mediate disease pathogenesis in the Ndufs4(KO) mouse model of Leigh syndrome
Julia C. Stokes, Rebecca L. Bornstein, Katerina James, Kyung Yeon Park, Kira A. Spencer, Katie Vo, John C. Snell, Brittany M. Johnson, Philip G. Morgan, Margaret M. Sedensky, Nathan A. Baertsch, Simon C. Johnson
Julia C. Stokes, Rebecca L. Bornstein, Katerina James, Kyung Yeon Park, Kira A. Spencer, Katie Vo, John C. Snell, Brittany M. Johnson, Philip G. Morgan, Margaret M. Sedensky, Nathan A. Baertsch, Simon C. Johnson
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Research Article Inflammation Neuroscience

Leukocytes mediate disease pathogenesis in the Ndufs4(KO) mouse model of Leigh syndrome

Abstract

Symmetric, progressive, necrotizing lesions in the brainstem are a defining feature of Leigh syndrome (LS). A mechanistic understanding of the pathogenesis of these lesions has been elusive. Here, we report that leukocyte proliferation is causally involved in the pathogenesis of LS. Depleting leukocytes with a colony-stimulating factor 1 receptor inhibitor disrupted disease progression, including suppression of CNS lesion formation and a substantial extension of survival. Leukocyte depletion rescued diverse symptoms, including seizures, respiratory center function, hyperlactemia, and neurologic sequelae. These data reveal a mechanistic explanation for the beneficial effects of mTOR inhibition. More importantly, these findings dramatically alter our understanding of the pathogenesis of LS, demonstrating that immune involvement is causal in disease. This work has important implications for the mechanisms of mitochondrial disease and may lead to novel therapeutic strategies.

Authors

Julia C. Stokes, Rebecca L. Bornstein, Katerina James, Kyung Yeon Park, Kira A. Spencer, Katie Vo, John C. Snell, Brittany M. Johnson, Philip G. Morgan, Margaret M. Sedensky, Nathan A. Baertsch, Simon C. Johnson

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Figure 4

Pexidartinib dose dependently increases Ndufs4(KO) survival, with survival limited by drug toxicity rather than CNS disease.

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Pexidartinib dose dependently increases Ndufs4(KO) survival, with surviv...
(A and B) Survival and cause of death in Ndufs4(KO) mice treated with increasing doses of pexidartinib. (A) Survival curves. Black line — control-treated Ndufs4(KO). Red dotted, dashed, and solid lines — Ndufs4(KO) mice treated with 100, 200, or 300 mg/kg/d pexidartinib, respectively (n as in Figure 2, G–I). Purple dashed/dotted line — control animals treated with 300 mg/kg/d pexidartinib (n = 6). Gray dashed line — rapamycin life span (for reference, see Figure 1). (B) Median life spans and dosing data associated with A. ****P < 0.0001 by log-rank test (passing Bonferroni’s cutoff of P < 0.0167). (C) Cause of death for Ndufs4(KO) animals in control and pexidartinib treatment groups (all control animals on pexidartinib 300 mg/kg/d died of unknown causes with no overt signs of disease/illness). n as in A. (D) Plasma ALT and (E) plasma AST levels (see Supplemental Methods). Data represent mean, error bars ± SEM. *P < 0.05, **P < 0.005 by 1-way ANOVA with Tukey’s multiple-testing correction–adjusted P values for pairwise comparisons. n = 8, 3, and 4 for untreated controls and pexidartinib 300 mg/kg/d treated controls and Ndufs4(KO) animals, respectively. (F) A model for the pathogenesis of disease in LS (see Discussion). In this model, CNS lesions and many systemic sequelae are causally downstream of immune involvement. A central role for glutamatergic neurons in initiating disease has previously been identified (8, 40), while our findings here reveal a role for leukocytes in the pathogenesis of disease. In the model resulting from these combined data, the mechanisms underlying the benefits of rapamycin and of PKC inhibitors, previously shown to benefit the Ndufs4(KO) mouse, can be accounted for by their convergence with pexidartinib and IPI-549 on leukocyte suppression. Key remaining questions are presented in Discussion.