ArticleNeurobiology of disease2020
Dysregulation of Rac or Rho elicits death of motor neurons and activation of these GTPases is altered in the G93A mutant hSOD1 mouse model of amyotrophic lateral sclerosis.
Article in Neurobiology of disease, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 35 citations in OpenAlex.
- Guanine Nucleotide Exchange Factors and Small GTPases: Their Regulation and Functions, Diseases, and Therapeutic Targets.MedComm · 2025Review
- Rho kinase isoforms in neurodegeneration: from cellular functions to therapeutic targets.Molecular biology reports · 2025Review
- α-Cyclodextrin/Moringin Impacts Actin Cytoskeleton Dynamics with Potential Implications for Synaptic Organization: A Preliminary Transcriptomic Study in NSC-34 Motor Neurons.International journal of molecular sciences · 2025Article
- Use of Proteomics to Explore Biomarkers of Amyotrophic Lateral Sclerosis (ALS): Proof of Principle from Humanized SOD1 Mouse to Human ALS.ACS pharmacology & translational science · 2025Review
- Circular RNA expression in ALS is progressively deregulated and tissue-dependent.BMC genomics · 2025Article
- Targeting Neurodegeneration: The Emerging Role of Hybrid Drugs.Current drug targets · 2025Review
- Ras, RhoA, and vascular pharmacology in neurodevelopment and aging.Neurochemistry international · 2024Review
- Novel insights into RAGE signaling pathways during the progression of amyotrophic lateral sclerosis in RAGE-deficient SOD1 G93A mice.PloS one · 2024Article
- Role of Rho-associated kinases and their inhibitor fasudil in neurodegenerative diseases.Frontiers in neuroscience · 2024Review
- Tiam1 coordinates synaptic structural and functional plasticity underpinning the pathophysiology of neuropathic pain.Neuron · 2023Article
- RhoA-LIMK Signaling Axis Reveals Rostral-Caudal Plane and Spatial Dysregulation in the Brain of Alzheimer's Disease Mouse Models.Journal of Alzheimer's disease : JAD · 2023Article
- Crosstalk between the Rho and Rab family of small GTPases in neurodegenerative disorders.Frontiers in cellular neuroscience · 2023Review
- Dermcidin Enhances the Migration, Invasion, and Metastasis of Hepatocellular Carcinoma CellsJournal of clinical and translational hepatology · 2022Article
- Multitarget Hybrid Fasudil Derivatives as a New Approach to the Potential Treatment of Amyotrophic Lateral Sclerosis.Journal of medicinal chemistry · 2022Article
- Rac-maninoff and Rho-vel: The symphony of Rho-GTPase signaling at excitatory synapses.Small GTPases · 2022Article
- Immune Signaling Kinases in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).International journal of molecular sciences · 2021Review
- Article
- Roles of palmitoylation in structural long-term synaptic plasticity.Molecular brain · 2021Review
- Pharmacological Modulators of Small GTPases of Rho Family in Neurodegenerative Diseases.Frontiers in cellular neuroscience · 2021Article
- Evaluation of active Rac1 levels in cancer cells: A case of misleading conclusions from immunofluorescence analysis.The Journal of biological chemistry · 2020Article
Corrections and comments
- Erratum issued
Authors and funding
4 authors at 3 institutions in 1 country.
Funding
Abstract
Rho GTPases play a central role in neuronal survival; however, the antagonistic relationship between Rac and Rho in the regulation of motor neuron survival remains poorly defined. In the current study, we demonstrate that treatment with NSC23766, a selective inhibitor of the Rac-specific guanine nucleotide exchange factors, Tiam1 and Trio, is sufficient to induce the death of embryonic stem cell (ESC)-derived motor neurons. The mode of cell death is primarily apoptotic and is characterized by caspase-3 activation, de-phosphorylation of ERK5 and AKT, and nuclear translocation of the BH3-only protein Bad. As opposed to the inhibition of Rac, motor neuron cell death is also induced by constitutive activation of Rho, via a mechanism that depends on Rho kinase (ROCK) activity. Investigation of Rac and Rho in the G93A mutant, human Cu, Zn-superoxide dismutase (hSOD1) mouse model of amyotrophic lateral sclerosis (ALS), revealed that active Rac1-GTP is markedly decreased in spinal cord motor neurons of transgenic mice at disease onset and end-stage, when compared to age-matched wild type (WT) littermates. Furthermore, although there is no significant change in active RhoA-GTP, total RhoB displays a striking redistribution from motor neuron nuclei in WT mouse spinal cord to motor neuron axons in end-stage G93A mutant hSOD1 mice. Collectively, these data suggest that the intricate balance between pro-survival Rac signaling and pro-apoptotic Rho/ROCK signaling is critical for motor neuron survival and therefore, disruption in the balance of their activities and/or localization may contribute to the death of motor neurons in ALS.
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