Autism-associated variants of neuroligin 4X impair synaptogenic activity by various molecular mechanisms.
Takafumi Yumoto, Misaki Kimura, Ryota Nagatomo and 11 others
PMID 32873342WHAT IT FOUND
In cells, autism-linked neuroligin 4X variants impaired inhibitory synapse formation through misfolding or excessive cleavage.
Chemical chaperones or ADAM10 inhibitors restored synapse formation in these variants, but no patients were tested.
Key findings
01All tested autism and X-linked mental retardation associated NL4X variants impaired inhibitory synapse formation in cell cultures.
02The chemical chaperone 4PBA restored mature NL4X levels and synaptogenic activity in variants caused by protein misfolding.
03The ADAM10 inhibitor INCB3619 restored cell-surface NL4X and synapse formation in variants caused by excessive cleavage.
STILL TO COME
How it was doneWhat they found
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What it does not show
The study was conducted entirely in cell lines and cultured neurons; no human patients or animal models were tested. It remains unknown whether the observed cellular dysfunctions occur in individuals carrying these NLGN4X variants. The therapeutic compounds (4PBA and INCB3619) were only tested in vitro; their safety and efficacy in humans for ASD or XLMR are unproven. Global inhibition of ADAM10 by drugs like INCB3619 could have detrimental off-target effects because ADAM10 processes many other substrates. The molecular mechanisms for the Q162K and K378R variants were not identified.
Declared interests
Funding was provided by the Japan Society for the Promotion of Science, the Japan Agency for Medical Research and Development, and the School of Medicine, Keio University. No other conflicts of interest are declared in the provided text.
The easy way to misread this
Do not interpret the restoration of synapse formation in cell cultures as evidence that 4PBA or ADAM10 inhibitors are effective treatments for autism or speech/language impairments in patients. The study did not test these compounds in humans or animals with the disorder.