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 1

Isoform-specific inhibition of PI3K catalytic subunit p110γ, but not p110α, p110β, or p110δ, significantly attenuates disease in the Ndufs4(KO) mouse model of LS.

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Isoform-specific inhibition of PI3K catalytic subunit p110γ, but not p11...
(A) Age of cachexia (n = 31), clasping (n = 35), ataxia (n = 28), and circling (n = 20) onset and of death (n = 41) (see Methods for symptoms, replicates, scoring). (B and C) Survival (B) and life span and dosage data (C) for Ndufs4(KO) mice administered control chow (black, n = 41) or isoform-specific inhibitors of PI3K catalytic subunits: p110α/BYL719 (n = 13), p110β/GSK2636771 (n = 7), p110δ/CAL101 (n = 6), p110γ/IPI549 (n = 6). Rapamycin for reference (see refs. 4, 5); line, median for rapamycin. (C) Color key for B and D-G, dosing, and median life spans. ‡P = 0.017, **P < 0.005, and ****P < 0.0001, log-rank test (Bonferroni-corrected significance threshold, BCST: P < 0.015). (D-G) Clasping (D), ataxia (E), circling (F), and cachexia (G) in Ndufs4(KO) mice treated with BYL719 (n = 12, 10, 8, 16), GSK2636771 (n = 7, 7, 7, 7), CAL101 (n = 6, 6, 6, 6), or IPI549 (n = 7, 7, 7, 6). Treatment indicated by color (see C) and p110 α/β/δ/γ symbols. Control-treated ns as in A. *P < 0.015, **P < 0.005, ***P < 0.0005, and ****P < 0.0001 by log-rank test vs. untreated Ndufs4(KO) (BCST: P < 0.015). (H and I) Ndufs4(KO) weight by age and treatment (indicated by color and symbol; mTOR, ABI009 treatment); local regression (Lowess) curve overlaid. ns as in B. (J) Performance of Ndufs4(KO) mice on a rotarod assay. (K) Blood glucose by age (see Methods). (J and K) n provided as numbers within/above bars. *P < 0.015, **P < 0.005, ***P < 0.0005, and ****P < 0.0001 by Welch’s t test (treated vs. untreated BCST: P < 0.015; vs. baseline within same treatment BCST: P < 0.0167). For rotarod, when animals die before P80, t tests are interpreted as significant. (L) Cause of death in survival studies. n values as in A and B. (M and N) Growth rate P21–P35 (M) and maximum weight during life (N). ns indicated within bars. *P < 0.0033, ***P < 0.0005, and ****P < 0.0001, unpaired, unequal variances (Welch’s) t test (BCST: P < 0.0033). Data represent mean, error bars ± SEM, unless otherwise stated.