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A rare autism-associated MINT2/APBA2 mutation disrupts neurexin trafficking and synaptic function.
Sci Rep 2019; 9(1):6024SR

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.

Authors+Show Affiliations

Department of Biology, Boston University, 24 Cummington Mall, Boston, MA, 02215, USA.Department of Biology, Boston University, 24 Cummington Mall, Boston, MA, 02215, USA.Institute of Anatomy and Molecular Neurobiology, Westfälische Wilhelms-University, 48149, Münster, Germany.Institute of Anatomy and Molecular Neurobiology, Westfälische Wilhelms-University, 48149, Münster, Germany.Department of Biology, Boston University, 24 Cummington Mall, Boston, MA, 02215, USA.Institute of Anatomy and Molecular Neurobiology, Westfälische Wilhelms-University, 48149, Münster, Germany. Cluster of Excellence EXC 1003, Cells in Motion, 48149, Münster, Germany.Department of Biology, Boston University, 24 Cummington Mall, Boston, MA, 02215, USA.Department of Biology, Boston University, 24 Cummington Mall, Boston, MA, 02215, USA. aho1@bu.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30988517

Citation

Lin, Amy Y., et al. "A Rare Autism-associated MINT2/APBA2 Mutation Disrupts Neurexin Trafficking and Synaptic Function." Scientific Reports, vol. 9, no. 1, 2019, p. 6024.
Lin AY, Henry S, Reissner C, et al. A rare autism-associated MINT2/APBA2 mutation disrupts neurexin trafficking and synaptic function. Sci Rep. 2019;9(1):6024.
Lin, A. Y., Henry, S., Reissner, C., Neupert, C., Kenny, C., Missler, M., ... Ho, A. (2019). A rare autism-associated MINT2/APBA2 mutation disrupts neurexin trafficking and synaptic function. Scientific Reports, 9(1), p. 6024. doi:10.1038/s41598-019-42635-7.
Lin AY, et al. A Rare Autism-associated MINT2/APBA2 Mutation Disrupts Neurexin Trafficking and Synaptic Function. Sci Rep. 2019 Apr 15;9(1):6024. PubMed PMID: 30988517.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A rare autism-associated MINT2/APBA2 mutation disrupts neurexin trafficking and synaptic function. AU - Lin,Amy Y, AU - Henry,Shawna, AU - Reissner,Carsten, AU - Neupert,Christian, AU - Kenny,Connor, AU - Missler,Markus, AU - Beffert,Uwe, AU - Ho,Angela, Y1 - 2019/04/15/ PY - 2018/10/03/received PY - 2019/04/01/accepted PY - 2019/4/17/entrez PY - 2019/4/17/pubmed PY - 2019/4/17/medline SP - 6024 EP - 6024 JF - Scientific reports JO - Sci Rep VL - 9 IS - 1 N2 - 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. SN - 2045-2322 UR - https://www.unboundmedicine.com/medline/citation/30988517/A_rare_autism-associated_MINT2/APBA2_mutation_disrupts_neurexin_trafficking_and_synaptic_function L2 - http://dx.doi.org/10.1038/s41598-019-42635-7 DB - PRIME DP - Unbound Medicine ER -