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SIK3 suppresses neuronal hyperexcitability by regulating the glial capacity to buffer K⁺ and water.

ABSTRACT: Glial regulation of extracellular potassium (K⁺) helps to maintain appropriate levels of neuronal excitability. While channels and transporters mediating K⁺ and water transport are known, little is understood about upstream regulatory mechanisms controlling the glial capacity to buffer K⁺ and osmotically obliged water. Here we identify salt-inducible kinase 3 (SIK3) as the central node in a signal transduction pathway controlling glial K⁺ and water homeostasis in Drosophila Loss of SIK3 leads to dramatic extracellular fluid accumulation in nerves, neuronal hyperexcitability, and seizures. SIK3-dependent phenotypes are exacerbated by K⁺ stress. SIK3 promotes the cytosolic localization of HDAC4, thereby relieving inhibition of Mef2-dependent transcription of K⁺ and water transport molecules. This transcriptional program controls the glial capacity to regulate K⁺ and water homeostasis and modulate neuronal excitability. We identify HDAC4 as a candidate therapeutic target in this pathway, whose inhibition can enhance the K⁺ buffering capacity of glia, which may be useful in diseases of dysregulated K⁺ homeostasis and hyperexcitability.

SUBMITTER: Li H

PROVIDER: S-EPMC6891094 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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SIK3 suppresses neuronal hyperexcitability by regulating the glial capacity to buffer K+ and water.

Li Hailun H Russo Alexandra A DiAntonio Aaron A

The Journal of cell biology 20191023 12

Glial regulation of extracellular potassium (K+) helps to maintain appropriate levels of neuronal excitability. While channels and transporters mediating K+ and water transport are known, little is understood about upstream regulatory mechanisms controlling the glial capacity to buffer K+ and osmotically obliged water. Here we identify salt-inducible kinase 3 (SIK3) as the central node in a signal transduction pathway controlling glial K+ and water hom ...[more]

PMID: 31645458

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Project description:Globular glial tauopathy (GGT) is a progressive neurodegenerative disease involving the grey matter and white matter (WM) and characterized by neuronal deposition of hyper-phosphorylated, abnormally conformed, truncated, oligomeric 4Rtau in neurons and in glial cells forming typical globular astrocyte and oligodendrocyte inclusions (GAIs and GOIs, respectively) and coiled bodies. Present studies centre on four genetic GGT cases from two unrelated families bearing the P301T mutation in MAPT and one case of sporadic GGT (sGGT) and one case of GGT linked to MAPT K317M mutation, for comparative purposes. Clinical and neuropathological manifestations and biochemical profiles of phospho-tau are subjected to individual variations in patients carrying the same mutation, even in carriers of the same family, independently of the age of onset, gender, and duration of the disease. Immunohistochemistry, western blotting, transcriptomic, proteomics and phosphoproteomics, and intra-cerebral inoculation of brain homogenates to wild-type (WT) mice were the methods employed. In GGT cases linked to MAPT P301T mutation, astrocyte markers GFAP, ALDH1L1, YKL40 mRNA and protein, GJA1 mRNA, and AQ4 protein are significantly increased; glutamate transporter GLT1 (EAAT2) and glucose transporter (SLC2A1) decreased; mitochondrial pyruvate carrier 1 (MPC1) increased, and mitochondrial uncoupling protein 5 (UCP5) almost absent in GAIs in frontal cortex (FC). Expression of oligodendrocyte markers OLIG1 and OLIG2mRNA, and myelin-related genes MBP, PLP1, CNP, MAG, MAL, MOG, and MOBP are significantly decreased in WM; CNPase, PLP1, and MBP antibodies reveal reduction and disruption of myelinated fibres; and SMI31 antibodies mark axonal damage in the WM. Altered expression of AQ4, GLUC-t, and GLT-1 is also observed in sGGT and in GGT linked to MAPT K317M mutation. These alterations point to primary astrogliopathy and oligodendrogliopathy in GGT. In addition, GGT linked to MAPT P301T mutation proteotypes unveil a proteostatic imbalance due to widespread (phospho)proteomic dearrangement in the FC and WM, triggering a disruption of neuron projection morphogenesis and synaptic transmission. Identification of hyper-phosphorylation of variegated proteins calls into question the concept of phospho-tau-only alteration in the pathogenesis of GGT. Finally, unilateral inoculation of sarkosyl-insoluble fractions of GGT homogenates from GGT linked to MAPT P301T, sGGT, and GGT linked to MAPT K317M mutation in the hippocampus, corpus callosum, or caudate/putamen in wild-type mice produces seeding, and time- and region-dependent spreading of phosphorylated, non-oligomeric, and non-truncated 4Rtau and 3Rtau, without GAIs and GOIs but only of coiled bodies. These experiments prove that host tau strains are important in the modulation of cellular vulnerability and phenotypes of phospho-tau aggregates.

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SIK3 suppresses neuronal hyperexcitability by regulating the glial capacity to buffer K⁺ and water.

Publications

SIK3 suppresses neuronal hyperexcitability by regulating the glial capacity to buffer K<sup>+</sup> and water.

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