LMNB1 reduction is a potential therapeutic strategy in a mouse model of autosomal dominant leukodystrophy
Nathan Herdman, Kaveh Moradi, Bruce Nmezi, Anushe Munir, Krizchelle A. Magtoto, Fang Liu, Mara Sullivan, Xuemei Zeng, Thomas K. Karikari, Quasar S. Padiath
Nathan Herdman, Kaveh Moradi, Bruce Nmezi, Anushe Munir, Krizchelle A. Magtoto, Fang Liu, Mara Sullivan, Xuemei Zeng, Thomas K. Karikari, Quasar S. Padiath
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Research Article Genetics Neuroscience

LMNB1 reduction is a potential therapeutic strategy in a mouse model of autosomal dominant leukodystrophy

Abstract

Autosomal dominant leukodystrophy (ADLD) is a fatal adult-onset CNS demyelinating disorder for which no treatment exists. The majority of ADLD cases are caused by duplications of the lamin B1 (LMNB1) gene, resulting in increased LMNB1 expression. While reducing LMNB1 levels represents a logical therapeutic strategy, its efficacy has not been previously demonstrated in any in vivo model. Mouse models with oligodendrocyte-specific human LMNB1 (hLMNB1) overexpression recapitulate salient features of ADLD. Using a modified version of this model, where hLMNB1 can be inducibly downregulated, we demonstrated that hLMNB1 reduction can prevent or substantially ameliorate disease progression. Therapeutic effects were maximized when hLMNB1 reduction was induced before expected symptom onset, resulting in improvements in behavioral, biochemical, histopathological, and survival measures relative to those of untreated animals. Reducing hLMNB1 levels after symptom onset led to improved survival but mixed results for other disease phenotypes. In addition, we identified potential biomarkers that track disease progression. Furthermore, we demonstrated that near-complete knockdown of murine LMNB1 expression in adulthood did not result in any overt CNS phenotype. Together, these results provide a proof of concept supporting LMNB1 reduction as a therapeutic strategy and offer a rationale for treatments aimed at lowering levels of this protein in ADLD.

Authors

Nathan Herdman, Kaveh Moradi, Bruce Nmezi, Anushe Munir, Krizchelle A. Magtoto, Fang Liu, Mara Sullivan, Xuemei Zeng, Thomas K. Karikari, Quasar S. Padiath

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Figure 4

Reduction of hLMNB1 reduces proinflammatory signaling in Tg-flox;Cre (3M) and produces a mixed response in Tg-flox;Cre (6M) mice.

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Reduction of hLMNB1 reduces proinflammatory signaling in Tg-flox;Cre (3M...
(A) Representative cervical spinal cord sections stained with GFAP, APP, and DAPI with the boundary between white and gray matter represented by a dotted line. The schematic indicates the region imaged. GFAP labels astrocytes, and APP labels amyloid precursor proteins. Scale bar: 200 μm. (B and C) Quantification of the ratio of GFAP+ cells in gray to white matter (B) and total APP+ cells (C) relative to WT. Each point represents the average of 2 independent fields per mouse. n ≥ 4 per group. (D) Representative spinal cord sections stained with NeuN, IBA1, and DAPI. The schematic indicates the region imaged. NeuN labels neurons, and IBA1 labels microglia. Scale bar: 200 μm. (E and F) Quantification of total NeuN+ cells (E) and IBA1+ cells (F) relative to WT. Each point represents the average of at least 2 independent fields per mouse. n ≥ 4 per group. Statistical tests: (B, E, and F) 1-way ANOVA test with Tukey’s post hoc test; (C) Welch’s ANOVA test with Dunnett’s T3 post hoc test. Data are shown as mean ± SEM. *P < 0.05, **P < 0.01, ****P < 0.0001; nonsignificant comparisons are not shown.