Abstract
MINT2/APBA2 is a synaptic adaptor protein involved in excitatory synaptic transmission. Several nonsynonymous coding variants in MINT2 have been identified in autism spectrum disorders (ASDs); however, these rare variants have not been examined functionally and the pathogenic mechanisms are unknown. Here, we examined the synaptic effects of rat Mint2 N723S mutation (equivalent to autism-linked human MINT2 N722S mutation) which targets a conserved asparagine residue in the second PDZ domain of Mint2 that binds to neurexin-1α (Nrxn1α), a presynaptic cell-adhesion protein implicated in ASDs. We show the N723S mutation impairs Nrxn1α stabilization and trafficking to the membrane while binding to Nrxn1α remains unaffected. Using time-lapse imaging in primary mouse neurons, we found that the N723S mutant had more immobile puncta at neuronal processes compared to Mint2 wild type. We therefore, reasoned that the N723S mutant may alter the co-transport of Nrxn1α at axonal processes to presynaptic terminals. Indeed, we found the N723S mutation affected Nrxn1α localization at presynaptic terminals which correlated with a decrease in Nrxn-mediated synaptogenesis and miniature event frequency in excitatory synapses. Together, our data reveal Mint2 N723S leads to neuronal dysfunction, in part due to alterations in Nrxn1α surface trafficking and synaptic function of Mint2.
Highlights
Autism Spectrum Disorders (ASDs) comprise a heterogeneous group of neurodevelopmental disorders characterized by a complex genetic etiology and impairments in social skills, communication and repetitive behaviors
We found that the N723S mutation decreased Nrxn1α localization in axons and the presynaptic terminals of primary mouse neurons leading to alterations in Nrxn-mediated synaptogenesis and synaptic function
Because Mint[2] N723S disrupts a conserved asparagine residue in the second PDZ domain of Mint[2] showed a robust effect on Nrxn1α protein stability, we focused on the pathophysiological effect of this single mutation and how Mint[2] N723S may be associated with autism spectrum disorders (ASDs)
Summary
Autism Spectrum Disorders (ASDs) comprise a heterogeneous group of neurodevelopmental disorders characterized by a complex genetic etiology and impairments in social skills, communication and repetitive behaviors. An independent study examining gene expression differences in autism brain tissue identified MINT2 as one of four key molecules differentially coexpressed with CNTNAP1, CHRM1 and A2BP1 in brains[9] These genes are involved in synaptic function, vesicular transport and neuronal projection suggesting a complex interplay of genes from multiple pathways associated with ASDs9. Knockout of a single Mint[2] allele in mouse displays a deficit in social interaction supporting the role of Mint[2] in emotional and social development[22] These results suggest that Mint proteins are important for synaptic function and that loss of function leads to phenotypes consistent with those observed in ASDs. Here, we surveyed the seven nonsynonymous MINT2 coding variants identified by Babatz et al, 2009 to assess whether these rare individual variants in MINT2 affect protein expression. We found that the N723S mutation decreased Nrxn1α localization in axons and the presynaptic terminals of primary mouse neurons leading to alterations in Nrxn-mediated synaptogenesis and synaptic function
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