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Journal Article

Liver kinase B1 depletion from astrocytes worsens disease in a mouse model of multiple sclerosis

MPS-Authors
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Saher,  G.
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

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Spieth,  L.
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons182320

Nave,  K.-A.
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

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Citation

Kalinin, S., Meares, G. P., Lin, S. X., Pietruczyk, E. A., Saher, G., Spieth, L., et al. (2020). Liver kinase B1 depletion from astrocytes worsens disease in a mouse model of multiple sclerosis. Glia, 68(3), 600-616. doi:10.1002/glia.23742.


Cite as: https://hdl.handle.net/21.11116/0000-000A-CCE0-3
Abstract
Liver kinase B1 (LKB1) is a ubiquitously expressed kinase involved in the regulation
of cell metabolism, growth, and inflammatory activation. We previously reported that
a single nucleotide polymorphism in the gene encoding LKB1 is a risk factor for multi-
ple sclerosis (MS). Since astrocyte activation and metabolic function have important
roles in regulating neuroinflammation and neuropathology, we examined the serine/
threonine kinase LKB1 in astrocytes in a chronic experimental autoimmune encepha-
lomyelitis mouse model of MS. To reduce LKB1, a heterozygous astrocyte-selective
conditional knockout (het-cKO) model was used. While disease incidence was similar,
disease severity was worsened in het-cKO mice. RNAseq analysis identified Kyoto
Encyclopedia of Genes and Genomes (KEGG) pathways enriched in het-cKO mice
relating to mitochondrial function, confirmed by alterations in mitochondrial complex
proteins and reductions in mRNAs related to astrocyte metabolism. Enriched path-
ways included major histocompatibility class II genes, confirmed by increases in
MHCII protein in spinal cord and cerebellum of het-cKO mice. We observed
increased numbers of CD4+ Th17 cells and increased neuronal damage in spinal
cords of het-cKO mice, associated with reduced expression of choline
acetyltransferase, accumulation of immunoglobulin-γ, and reduced expression of fac-
tors involved in motor neuron survival. In vitro, LKB1-deficient astrocytes showed
reduced metabolic function and increased inflammatory activation. These data sug-
gest that metabolic dysfunction in astrocytes, in this case due to LKB1 deficiency,
can exacerbate demyelinating disease by loss of metabolic support and increase in
the inflammatory environment.