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Cited by 46Genetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology ResearchProtein Kinase Regulation and GTPase Signaling

Actin-Dependent Alterations of Dendritic Spine Morphology in Shankopathies

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Sarowar, Tasnuva, Grabrucker, Andreas M.·2016·Neural Plasticity
DOI 10.1155/2016/8051861PMC PMC5067329
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Abstract

Shank proteins (Shank1, Shank2, and Shank3) act as scaffolding molecules in the postsynaptic density of many excitatory neurons. Mutations in SHANK genes, in particular SHANK2 and SHANK3, lead to autism spectrum disorders (ASD) in both human and mouse models. Shank3 proteins are made of several domains—the Shank/ProSAP N-terminal (SPN) domain, ankyrin repeats, SH3 domain, PDZ domain, a proline-rich region, and the sterile alpha motif (SAM) domain. Via various binding partners of these domains, Shank3 is able to bind and interact with a wide range of proteins including modulators of small GTPases such as RICH2, a RhoGAP protein, and β PIX, a RhoGEF protein for Rac1 and Cdc42, actin binding proteins and actin modulators. Dysregulation of all isoforms of Shank proteins, but especially Shank3, leads to alterations in spine morphogenesis, shape, and activity of the synapse via altering actin dynamics. Therefore, here, we highlight the role of Shank proteins as modulators of small GTPases and, ultimately, actin dynamics, as found in multiple in vitro and in vivo models. The failure to mediate this regulatory role might present a shared mechanism in the pathophysiology of autism-associated mutations, which leads to dysregulation of spine morphogenesis and synaptic signaling.

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  • Rac1 is a converging factor downstream of numerous proteins encoded by high-risk ASD genes.

    “Rac1 has been identified as a converging factor downstream of numerous proteins encoded by high-risk ASD genes, such as SHANK 4–6, FMR1 (fragile X mental retardation-1) 7, 8, NRXN 9, and AUTS2 10.”

    From Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function. (2021) · cites this paper as [5]

    Section 5 describes SHANK3 interactions that regulate Rac1 and reports reduced Rac1 activity in Shank3-knockout mice, supporting the SHANK example. But section 4 calls FMRP an indirect downstream effector of Rac1—the reverse of the claimed direction—and the cited passages do not establish Rac1 as downstream of NRXN or AUTS2. The paper therefore supports part of the proposed convergence, not the full claim. (LLM, conf=0.84)

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Cited by

Sorted by citations

Authors
Sarowar, T., & Grabrucker, A. M.
Affiliations
Universität Ulm (DE)
Corresponding author
Grabrucker, Andreas M.
ORCID
Grabrucker, Andreas M.
Venue
Neural Plasticity
Publisher
Wiley
Published
2016
Volume
2016
Pages
1-15
ISSN
  • 1687-5443 (ISSN-L)
  • 2090-5904
DOI
10.1155/2016/8051861
PMC
PMC5067329
OpenAlex
W2529454481
Cited by
46
References
17
Citations by year
2026: 2 · 2025: 2 · 2024: 1 · 2023: 6 · 2022: 6 · 2021: 7 · 2020: 6 · 2019: 7 · 2018: 4 · 2017: 5
FWCI
0.76
Type
journal article
Language
en
Open access
Licence
Locations
  • Neural Plasticity (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • University of Limerick Institutional Repository (University of Limerick) (acceptedVersion, cc-by-nc-sa)
  • University of Limerick Institutional Repository (University of Limerick) (acceptedVersion, other-oa)
  • Arrow@dit (Dublin Institute of Technology) (submittedVersion, cc-by-nc-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by-nc-sa)
  • University of Limerick Institutional Repository (University of Limerick)
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 › Protein Kinase Regulation and GTPase Signaling
Keywords
SHANK3, Shank2, Shank1, dendritic spine morphology, actin dynamics, autism spectrum disorder, postsynaptic density, small GTPases, RhoGAP, RhoGEF, betaPIX, synaptic signaling, actin-binding proteins
MeSH terms
Actins, Animals, Autistic Disorder, Humans, Nerve Tissue Proteins, Presynaptic Terminals, GTP Phosphohydrolases, Dendritic Spines

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