Shank3 oligomerization governs material properties of the postsynaptic density condensate and synaptic plasticity
Abstract
Cells contain numerous types of membraneless organelles or biological condensates formed via phase separation. Cellular biological condensates have broad material properties ranging from Newtonian fluids to elastic solids. How the material property of a biological condensate is regulated for cellular functions is poorly understood. Here, we discovered that, like native postsynaptic densities (PSDs), the reconstituted PSD condensate forms a soft glass material without signs of irreversible amyloid structure formation. Such glass-like PSD condensate formation is based on percolation of the PSD protein network via specific and multivalent interactions among scaffold proteins. Disruption of Shank3 SAM domain-mediated oligomerization, one type of SHANK3 mutation observed in Phelan-McDermid syndrome patients, softened the PSD condensate by weakening its network percolation, impaired synaptic transmission and plasticity, and caused autistic-like behavior in mice. Thus, our study suggests that the material properties of the PSD condensate are critical for learning and memory mediated by neuronal synapses.
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SHANK3 mutations, particularly deletions or loss-of-function variants, are associated with Phelan-McDermid syndrome.
“SHANK3 mutations, particularly deletions or loss-of-function variants, are associated with Phelan-McDermid syndrome (Jia et al., 2025).”
From Biological hierarchy from genotype to phenotype in syndromic and non-syndromic autism spectrum disorder (2026) · cites this paper as Jia et al., 2025
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Qing, Z., Yin, Z., Chen, B., Rao, Z., Yin, D., Li, D., Lu, Y., Shi, M., Li, S., Xu, Y., et al. (2026) · Frontiers in Neuroscience · doi:10.3389/fnins.2026.1964684
“Postsynaptic Scaffold and Adhesion Molecules: Within the post-synaptic density (PSD) of excitatory synapses, SHANK2 and SHANK3 encode scaffold proteins.”
InfluentialSelf-citation
- Authors
- Jia, B., Shen, Z., Zhu, S., Huang, J., Liao, Z., Zhao, S., Li, H., Chen, S., Xu, Y., Wang, Y., Peng, H., Bai, G., Lu, Y., Tong, P., Tao, W., & Zhang, M.
- Affiliations
- Hong Kong University of Science and Technology (HK)
- Fujian Medical University (CN)
- Huazhong University of Science and Technology (CN)
- Southern University of Science and Technology (CN)
- Corresponding author
- Zhang, Mingjie
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2025-11
- Volume
- 188
- Issue
- 23
- Pages
- 6473-6491.e21
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W4413421622
- Cited by
- 25
- References
- 10
- Citations by year
- 2026: 19 · 2025: 6
- FWCI
- 14.78
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- National Natural Science Foundation of China
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- SHANK3, postsynaptic density, phase separation, soft glass, material properties, multivalent interactions, SAM domain, oligomerization, Phelan-McDermid syndrome, synaptic plasticity, synaptic transmission, autism-like behavior, learning and memory
- MeSH terms
- Animals, Autistic Disorder, Chromosome Deletion, Chromosomes, Human, Pair 22, Humans, Microfilament Proteins, Mutation, Nerve Tissue Proteins, Synaptic Transmission, Neuronal Plasticity, Neurons, Synapses, Chromosome Disorders, Mice, Post-Synaptic Density
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