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Cited by 103Protein Kinase Regulation and GTPase SignalingAlzheimer's disease research and treatmentsCellular transport and secretion

Small GTPases of the Ras and Rho Families Switch on/off Signaling Pathways in Neurodegenerative Diseases

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Arrazola Sastre, Alazne, Luque Montoro, Miriam, Gálvez-Martín, Patricia, Lacerda, Hadriano M, Lucia, Alejandro, Llavero, Francisco, Zugaza, José Luis·2020·International Journal of Molecular Sciences
DOI 10.3390/ijms21176312PMC PMC7504559
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Abstract

Small guanosine triphosphatases (GTPases) of the Ras superfamily are key regulators of many key cellular events such as proliferation, differentiation, cell cycle regulation, migration, or apoptosis. To control these biological responses, GTPases activity is regulated by guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and in some small GTPases also guanine nucleotide dissociation inhibitors (GDIs). Moreover, small GTPases transduce signals by their downstream effector molecules. Many studies demonstrate that small GTPases of the Ras family are involved in neurodegeneration processes. Here, in this review, we focus on the signaling pathways controlled by these small protein superfamilies that culminate in neurodegenerative pathologies, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Specifically, we concentrate on the two most studied families of the Ras superfamily: the Ras and Rho families. We summarize the latest findings of small GTPases of the Ras and Rho families in neurodegeneration in order to highlight these small proteins as potential therapeutic targets capable of slowing down different neurodegenerative diseases.

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  • Dysregulation of Rho GTPases has been studied in relation to cancer progression, but accumulating evidence supports a role in traumatic brain injury and neurodegenerative diseases.

    “Dysregulation of Rho GTPases has been studied in relation to cancer progression for a number of years [3], but accumulating evidence supports a role in traumatic brain injury and neurodegenerative diseases as well [4,5,6,7].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [5]

    Section 3, “Small GTPases of the Rho Family” (page not provided), says Rho GTPases play an important role in neurodegenerative processes, including those associated with Alzheimer’s and Parkinson’s diseases. Our copy does not address traumatic brain injury, so it supports only the neurodegenerative-disease part of the claim. The cancer-progression clause is attached to a different citation [3]. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • GEFs catalyze the exchange of GDP for GTP, leading to conformational changes in switch I and switch II regions required for activation of small GTPases.

    “In response to extracellular stimuli emanating from cell surface receptors, guanine nucleotide exchange factors (GEFs) catalyze the exchange of GDP for GTP, leading to the conformational changes in the switch I and switch II regions required for activation of the small GTPases.”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [5]

    The Introduction states that GEFs promote GDP release and GTP binding, shifting small GTPases from an inactive to an active state. It also places small GTPases in signaling responses to extracellular stimuli, but does not identify conformational changes in switch I and switch II as the mechanism of activation. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Emerging evidence points toward a role of aberrant RhoA signaling in neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis.

    “Indeed, emerging evidence points toward a role of aberrant RhoA signaling in neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis.”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [5]

    Section 3.1 (RhoA; page not supplied) links RhoA and RhoA/ROCK signaling to Alzheimer’s and Parkinson’s disease. The review’s Introduction says it focuses on those two diseases; the passages found do not support extending the claim to Huntington’s disease or amyotrophic lateral sclerosis. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • GAPs enhance the intrinsic GTPase activity of small GTPases, resulting in GTP hydrolysis to GDP and inorganic phosphate and inactivation of the GTPases.

    “Conversely, GTPase-activating proteins (GAPs) enhance the relatively slow intrinsic GTPase activity of the small GTPases, resulting in GTP hydrolysis to GDP and inorganic phosphate (Pi) and inactivation of the GTPases [5,14].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [5]

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Cited by

Sorted by citations

Authors
Arrazola Sastre, A., Luque Montoro, M., Gálvez-Martín, P., Lacerda, H. M., Lucia, A., Llavero, F., & Zugaza, J. L.
Affiliations
  • Achucarro Basque Center for Neuroscience, Science Park of the Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU), 48940 Leioa, Spain
  • Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Granada, 180041 Granada, Spain
  • University of the Basque Country (ES)
  • Faculty of Sport Science, European University of Madrid, 28670 Madrid, Spain
Corresponding author
Llavero, Francisco
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2020-08-31
Volume
21
Issue
17
Pages
6312
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms21176312
PMC
PMC7504559
OpenAlex
W3082256611
Cited by
103
References
11
Citations by year
2026: 11 · 2025: 14 · 2024: 26 · 2023: 22 · 2022: 15 · 2021: 12 · 2020: 2 · 2016: 1
FWCI
1.24
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Institutional Repository of the University of Granada (University of Granada) (submittedVersion, cc-by)
  • ABACUS. Repositorio de Producción Científica (Universidad Europea) (submittedVersion, cc-by-nc-nd)
  • Communities in ADDI (Universidad del Pais Vasco) (submittedVersion, other-oa)
  • Communities in ADDI (University of the Basque Country) (submittedVersion, other-oa)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-nd)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Hispana (submittedVersion, cc-by)
Funders
  • Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza (PRE_2017_1_0016)
  • Instituto de Salud Carlos III (PI18/00207)
  • Euskal Herriko Unibertsitatea (US19/04)
  • Foundation Jesús de Gangoiti y Barrera (45832736S)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords
small GTPases, Ras superfamily, Rho family, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, guanine nucleotide exchange factor, GTPase-activating protein, guanine nucleotide dissociation inhibitor, signal transduction, therapeutic target
MeSH terms
Animals, Humans, Signal Transduction, ras Proteins, Neurodegenerative Diseases, Monomeric GTP-Binding Proteins, rho GTP-Binding Proteins

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