| First Author | Hassani Nia F | Year | 2020 |
| Journal | Mol Autism | Volume | 11 |
| Issue | 1 | Pages | 85 |
| PubMed ID | 33115499 | Mgi Jnum | J:331656 |
| Mgi Id | MGI:6780815 | Doi | 10.1186/s13229-020-00385-8 |
| Citation | Hassani Nia F, et al. (2020) Targeting of delta-catenin to postsynaptic sites through interaction with the Shank3 N-terminus. Mol Autism 11(1):85 |
| abstractText | BACKGROUND: Neurodevelopmental disorders such as autism spectrum disorder (ASD) may be caused by alterations in genes encoding proteins that are involved in synapse formation and function. This includes scaffold proteins such as Shank3, and synaptic adhesion proteins such as Neurexins or Neuroligins. An important question is whether the products of individual risk genes cooperate functionally (exemplified in the interaction of Neurexin with Neuroligin isoforms). This might suggest a common pathway in pathogenesis. For the SHANK3 gene, heterozygous loss of function, as well as missense mutations have been observed in ASD cases. Several missense mutations affect the N-terminal part of Shank3 which contains the highly conserved Shank/ProSAP N-terminal (SPN) and Ankyrin repeat (Ank) domains. The role of these domains and the relevance of these mutations for synaptic function of Shank3 are widely unknown. METHODS: We used purification from a synaptic protein fraction, as well as a variety of biochemical and cell biological approaches to identify proteins which associate with the Shank3 N-terminus at postsynaptic sites. RESULTS: We report here that delta-catenin, which is encoded by CTNND2, an autism candidate gene, directly interacts with the Ank domain of Shank3 at postsynaptic sites through its Armadillo-repeat domain. The interaction is not affected by well-known posttranslational modifications of delta-catenin, i.e. by phosphorylation or palmitoylation. However, an ASD-associated mutation in the SPN domain of Shank3, L68P, significantly increases the interaction of Shank3 with delta-catenin. By analysis of postsynaptic fractions from mice, we show that the lack of SPN-Ank containing, large isoforms of Shank3 results in the loss of postsynaptic delta-catenin. Further, expression of Shank3 variants containing the N-terminal domains in primary cultured neurons significantly increased the presence of coexpressed delta-catenin at postsynaptic sites. LIMITATIONS: Work in model organisms such as mice, and in primary cultured neurons may not reproduce faithfully the situation in human brain neurons. Work in primary cultured neurons was also hampered by lack of a specific antibody for endogenous delta-catenin. CONCLUSIONS: Our data show that the interaction between Shank3 N-terminus and delta-catenin is required for the postsynaptic targeting of delta-catenin. Failure of proper targeting of delta-catenin to postsynaptic sites may contribute to the pathogenesis of autism spectrum disorder. |
