Neurodevelopmental disorder–associated mutations in TAOK1 reveal its function as a plasma membrane remodeling kinase

Abstract

Mutations in TAOK1 , which encodes a serine-threonine kinase, are associated with both autism spectrum disorder (ASD) and neurodevelopmental delay (NDD). Here, we investigated the molecular function of this evolutionarily conserved kinase and the mechanisms through which TAOK1 mutations may lead to neuropathology. We found that TAOK1 was abundant in neurons in the mammalian brain and remodeled the neuronal plasma membrane through direct association with phosphoinositides. Our characterization of four NDD-associated TAOK1 mutations revealed that these mutants were catalytically inactive and were aberrantly trapped in a membrane-bound state, which induced abnormal membrane protrusions. Expression of these TAOK1 mutants in cultured mouse hippocampal neurons led to abnormal growth of the dendritic arbor. The coiled-coil region carboxyl-terminal to the kinase domain was predicted to fold into a triple helix, and this region directly bound phospholipids and was required for both membrane association and induction of aberrant protrusions. Autophosphorylation of threonine-440 and threonine-443 in the triple-helical region by the kinase domain blocked the plasma membrane association of TAOK1. These findings define TAOK1 as a plasma membrane remodeling kinase and reveal the underlying mechanisms through which TAOK1 dysfunction may lead to neurodevelopmental disorders.

Heterozygous truncating variant of TAOK1 in a boy with periventricular nodular heterotopia: a case report and literature review of TAOK1-related neurodevelopmental disorders

“…The finding cortical migration defects such as of PVNH is highly consistent with the cellular and developmental role of TAOK1 in neuronal migration, as defined by previous functional studies both in vitro and in animal models [ 4 , 11 , 13 , 14 ].…”

“…Although large–scale WES and array-CGH studies had already identified TAOK1 as a candidate gene for NDDs since 2011 [ 9 , 10 ], the direct association has been confirmed only recently [ 11 , 12 ]. Some of these studies clearly documented that defects in TAOK1 expression can affect neuronal maturation and cortical development both in vitro and in animal models [ 4 , 11 , 13 , 14 ].…”

Retrospective model utilizing biopsies, granulosa cells, and polar body to predict oocyte competence in bovine

“…Together, the mitochondrial related genes with granulosa/oocyte Cellular Component enrichment (mitochondrial pathways and high energetic dependent pathways egg: spindle) converged to the idea that this non competent oocyte and associated cells in follicle are molecularly delayed, as previously stated, and mature oocytes have low mitochondrial activity (Beeman et al, 2023). Still, in the oocyte, we may find pathways that support our ideas, such as DNA replication, TGF-Beta, and nucleocytoplasmic transport.…”

“…Reinforcing this, we found the gene TAOK1 (TAO kinase 1) as a DEG, and at the same time methylated in the BL group suggesting that his expression occurred possible during or before maturation and must be repressed at the end of oocyte maturation. This gene triggers microtubules instability and disassembly in neuronal studies (Beeman et al, 2023).…”

STRIPAK controls cell-cell communication by promoting cytoneme biogenesis through the membrane-sculpting function of Slik

“…This membrane sculpting function might be conserved, as among the forty-seven human Ste20 kinases, SLK and LOK, the two human orthologues of Slik, as well as Tao1 and Tao3, are predicted to feature a C-terminus with the three bundled alpha-helices characteristic of Slik. Recently, Tao1 was shown to promote the growth of neuron dendritic arbor (Beeman et al, 2023). There was speculation that Tao1 could remodel membranes through its potential BAR domain, although this was not experimentally tested.…”