Mutations in autism-linked gene trigger membrane mischief

Spiky floor: Cultured kidney cells expressing mutated TAOK1 develop a plethora of irregular extensions of the cell-surface membrane.

Picture courtesy of Smita Yadav

The neuronal membrane is a dynamic place. It frequently shifts its form, bulging outward to sprout antenna that information cell motion or branches that join with different neurons, in a course of orchestrated by membrane-remodeling proteins.

TAOK1, a gene strongly linked to autism and different neurodevelopmental circumstances, helps to mildew the membrane, and mutations within the gene deform the neuronal floor, a brand new examine reveals. These irregularities may contribute to core traits related to TAOK1 mutations, comparable to mental incapacity.

The gene belongs to a household of three TAO kinases that add phosphate teams to signaling proteins. All three enzymes contribute to mind growth, and mutations that disrupt their operate have been linked to autism in earlier work. As an example, TAOK2, positioned on a piece of chromosome 16 that’s lacking in some autistic folks, regulates neuronal migration.

“When folks discuss TAOKs, they sort of lump them altogether and consider them as doing the identical factor,” says lead investigator Smita Yadav, assistant professor of pharmacology on the College of Washington in Seattle. “However our work reveals that they’re very totally different proteins, doing very various things.”

Earlier research hinted at TAOK1’s potential function in neuronal wiring. Turning up TAOK1 gene ranges in mice distorts dendritic spines, and depleting the invertebrate model of the protein in fruit flies results in overgrown dendrites and hyperconnectivity. However how TAOK1 mutations set off connectivity modifications was unclear.

Within the new examine, the researchers targeted on 4 mutations which are linked to autism or different neurodevelopmental circumstances and that stop TAOK1 from phosphorylating its targets. Cultured neurons and human kidney cells that specific these “kinase-dead” variations of the gene sprouted tentacle-like protrusions over all the cell floor, the group discovered. The buildings hyperextended till they broke off, littering the tradition medium with particles.

Additional investigation revealed that TAOK1 binds to the plasma membrane and dissociates by attaching a phosphate group to itself. Unable to autophosphorylate, the kinase-dead mutants can’t change themselves off to tear away from the membrane. Trapped on the cell floor, TAOK1 mutants excessively form the cell’s outer layer, coating it with protrusions.

Picture courtesy of N. Beeman, et al.

“It’s attention-grabbing that TAOK1 and TAOK2 are so complementary and have overlapping features, however have very totally different roles as effectively,” says Karun Singh, affiliate professor of biochemistry and biomedical science at McMaster College in Hamilton, Canada, who was not concerned within the examine. “It undoubtedly warrants additional investigation,” he says.

The findings had been revealed on 3 January in Science Signaling.

Cells expressing mutated TAOK1 grew dendrites with fewer, shorter branches, suggesting that altered membrane transforming may have an effect on synapse formation. Protrusions may additionally lead synaptic proteins, comparable to AMPA receptors, astray, Yadav says. However future research are wanted to verify whether or not membrane contortions underlie the connectivity modifications seen in animal fashions, she provides.

“Mechanistically talking, they actually nailed down at the least one of many roles of TAOK1,” says Froylan Calderón de Anda, head of the neuronal growth analysis group on the College Medical Centre Hamburg-Eppendorf in Germany, who didn’t participate within the examine. However extra knowledge, ideally from animal fashions, is required to find out how the irregular buildings have an effect on neuronal wiring, he says.

Yadav’s group plans to additional examine the results of TAOK1 mutations in cells that higher mirror how these mutations happen in folks, who usually carry just one disrupted copy; to date, the researchers have used cells containing two practical copies and a mutated model expressed at artificially excessive ranges. The subsequent step, Yadav says, is to mutate a single gene copy utilizing CRISPR in neurons grown from human stem cells.

Doing so will allow the group to check the potential of kinase-activating medicine. “Protein kinases are excellent drug targets,” says Patrick Eyers, professor of biochemistry on the College of Liverpool in the UK, who was not concerned within the examine. Molecules that may reshape TAOK1 could reactivate the protein and assist sculpt the plasma membrane, he provides. Genetic approaches that improve expression of the practical copy, comparable to antisense oligonucleotides, may additionally present potential, Yadav says.

The researchers are additionally probing the results of TAOK1 mutations that don’t inhibit kinase exercise. Unpublished work by the lab suggests these have distinct results, which is perhaps mapped to distinct traits. This end result implies {that a} remedy concentrating on one mutation is probably not efficient for all, Yadav says.

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