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Cited by 83Genetics and Neurodevelopmental DisordersProtein Kinase Regulation and GTPase SignalingNeuroscience and Neuropharmacology Research

Rho GTPases in Intellectual Disability: From Genetics to Therapeutic Opportunities

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Zamboni, Valentina, Jones, Rebecca, Umbach, Alessandro, Ammoni, Alessandra, Passafaro, Maria, Hirsch, Emilio, Merlo, Giorgio R.·2018·International Journal of Molecular Sciences
DOI 10.3390/ijms19061821PMC PMC6032284
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Abstract

Rho-class small GTPases are implicated in basic cellular processes at nearly all brain developmental steps, from neurogenesis and migration to axon guidance and synaptic plasticity. GTPases are key signal transducing enzymes that link extracellular cues to the neuronal responses required for the construction of neuronal networks, as well as for synaptic function and plasticity. Rho GTPases are highly regulated by a complex set of activating (GEFs) and inactivating (GAPs) partners, via protein:protein interactions (PPI). Misregulated RhoA, Rac1/Rac3 and cdc42 activity has been linked with intellectual disability (ID) and other neurodevelopmental conditions that comprise ID. All genetic evidences indicate that in these disorders the RhoA pathway is hyperactive while the Rac1 and cdc42 pathways are consistently hypoactive. Adopting cultured neurons for in vitro testing and specific animal models of ID for in vivo examination, the endophenotypes associated with these conditions are emerging and include altered neuronal networking, unbalanced excitation/inhibition and altered synaptic activity and plasticity. As we approach a clearer definition of these phenotype(s) and the role of hyper- and hypo-active GTPases in the construction of neuronal networks, there is an increasing possibility that selective inhibitors and activators might be designed via PPI, or identified by screening, that counteract the misregulation of small GTPases and result in alleviation of the cognitive condition. Here we review all knowledge in support of this possibility.

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  • Within the central nervous system, Rho GTPases have been implicated in nearly all steps of brain development.

    “Within the central nervous system, Rho GTPases have been implicated in nearly all steps of brain development [9].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [9]

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Sorted by citations

Authors
Zamboni, V., Jones, R., Umbach, A., Ammoni, A., Passafaro, M., Hirsch, E., & Merlo, G. R.
Affiliations
  • University of Turin (IT)
  • National Research Council (IT)
Corresponding author
Merlo, Giorgio R.
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2018-06-20
Volume
19
Issue
6
Pages
1821
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms19061821
PMC
PMC6032284
OpenAlex
W2809668203
Cited by
83
References
11
Citations by year
2026: 5 · 2025: 2 · 2024: 11 · 2023: 12 · 2022: 16 · 2021: 13 · 2020: 16 · 2019: 6 · 2018: 2
FWCI
1.28
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
Rho GTPases, intellectual disability, RhoA, Rac1, Cdc42, GEF, GaP, protein-protein interaction, brain development, neuronal network formation, synaptic plasticity, excitation-inhibition balance, therapeutic target
MeSH terms
Animals, Enzyme Inhibitors, Humans, Intellectual Disability, Neuronal Plasticity, Neurons, Guanine Nucleotide Exchange Factors, GTPase-Activating Proteins, rho GTP-Binding Proteins, Models, Animal, Mice, Rats, Neurogenesis

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