Mutations in Autism-Linked Gene TAOK1 Cause Membrane Mischief

Good news! Progress in this area of research is very slow and piecemeal!

"... TAOK1, a gene strongly linked to autism and other neurodevelopmental conditions, helps to mold the membrane, and mutations in the gene deform the neuronal surface, a new study shows. Those irregularities could contribute to core traits associated with TAOK1 mutations, such as intellectual disability.

The gene belongs to a family of three TAO kinases that add phosphate groups to signaling proteins. All three enzymes contribute to brain development, and mutations that disrupt their function have been linked to autism in earlier work. ..."

From the 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."

Mutations in Autism-Linked Gene Cause Membrane Mischief | The Scientist Magazine® Inactivating TAOK1 prompts tentacle-like protrusions to form all over a neuron’s surface, revealing the gene’s role in molding the membrane.

Neurodevelopmental disorder–associated mutations in TAOK1 reveal its function as a plasma membrane remodeling kinase (no public access)

Shape shifter: TAOK1 (blue) binds to and molds the plasma membrane in hippocampal neurons from rat embryos.