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

Stankiewicz, Trisha R.; Peña, Claudia; Bouchard, Ron J.; Linseman, Daniel A.

doi:10.1016/j.nbd.2020.104743

Cited by 21 publications

(21 citation statements)

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“…Most of the studies regarding the functional roles of palmitoylation have been carried out in brain neurons. A recent study [347] showing that Rho GTPases including Rac1, RhoA and RhoB are involved in the neurite integrity and motor neuron survival in the spinal cord in a mouse model of amyotrophic lateral sclerosis, provides hints on the role of small GTPase-regulated structural changes in the spinal cord physiology. Studies performed on spinal cord neurons have shed light on the roles of palmitoylation in spinal cord development and spinal cord-related diseases as well [90,[348][349][350].…”

Section: Discussionmentioning

confidence: 99%

Roles of palmitoylation in structural long-term synaptic plasticity

Skup

2021

Mol Brain

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Long-term potentiation (LTP) and long-term depression (LTD) are important cellular mechanisms underlying learning and memory processes. N-Methyl-d-aspartate receptor (NMDAR)-dependent LTP and LTD play especially crucial roles in these functions, and their expression depends on changes in the number and single channel conductance of the major ionotropic glutamate receptor α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) located on the postsynaptic membrane. Structural changes in dendritic spines comprise the morphological platform and support for molecular changes in the execution of synaptic plasticity and memory storage. At the molecular level, spine morphology is directly determined by actin cytoskeleton organization within the spine and indirectly stabilized and consolidated by scaffold proteins at the spine head. Palmitoylation, as a uniquely reversible lipid modification with the ability to regulate protein membrane localization and trafficking, plays significant roles in the structural and functional regulation of LTP and LTD. Altered structural plasticity of dendritic spines is also considered a hallmark of neurodevelopmental disorders, while genetic evidence strongly links abnormal brain function to impaired palmitoylation. Numerous studies have indicated that palmitoylation contributes to morphological spine modifications. In this review, we have gathered data showing that the regulatory proteins that modulate the actin network and scaffold proteins related to AMPAR-mediated neurotransmission also undergo palmitoylation and play roles in modifying spine architecture during structural plasticity.

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Section: Discussionmentioning

confidence: 99%

Roles of palmitoylation in structural long-term synaptic plasticity

Skup

2021

Mol Brain

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“…This concept is supported by the recent studies that Rac1 selective inhibitor NSC23766 induced motor neuron apoptosis. Whereas RhoA/ROCK is overactivated, Rac1-GTP is decreased, and RhoB is redistributed in a well- established G93A mutant, human Cu, Zn-superoxide dismutase (hSOD1) ALS mouse model (Stankiewicz et al, 2020 ).…”

Section: Als and Spinal Muscular Atrophy (Sma)mentioning

confidence: 99%

Pharmacological Modulators of Small GTPases of Rho Family in Neurodegenerative Diseases

Guiler

Koehler

Boykin

et al. 2021

Front. Cell. Neurosci.

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Classical Rho GTPases, including RhoA, Rac1, and Cdc42, are members of the Ras small GTPase superfamily and play essential roles in a variety of cellular functions. Rho GTPase signaling can be turned on and off by specific GEFs and GAPs, respectively. These features empower Rho GTPases and their upstream and downstream modulators as targets for scientific research and therapeutic intervention. Specifically, significant therapeutic potential exists for targeting Rho GTPases in neurodegenerative diseases due to their widespread cellular activity and alterations in neural tissues. This study will explore the roles of Rho GTPases in neurodegenerative diseases with focus on the applications of pharmacological modulators in recent discoveries. There have been exciting developments of small molecules, nonsteroidal anti-inflammatory drugs (NSAIDs), and natural products and toxins for each classical Rho GTPase category. A brief overview of each category followed by examples in their applications will be provided. The literature on their roles in various diseases [e.g., Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic lateral sclerosis (ALS), Frontotemporal dementia (FTD), and Multiple sclerosis (MS)] highlights the unique and broad implications targeting Rho GTPases for potential therapeutic intervention. Clearly, there is increasing knowledge of therapeutic promise from the discovery of pharmacological modulators of Rho GTPases for managing and treating these conditions. The progress is also accompanied by the recognition of complex Rho GTPase modulation where targeting its signaling can improve some aspects of pathogenesis while exacerbating others in the same disease model. Future directions should emphasize the importance of elucidating how different Rho GTPases work in concert and how they produce such widespread yet different cellular responses during neurodegenerative disease progression.

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“…Cells 2021, 10, 1604 of 13 We found that UNC-45A is enriched in the highly proliferating and prone to remodeling cells of the mouse reproductive system, in the microtubule-rich regions of the mouse central nervous system and in the cilia of both, the mouse reproductive system and the brain. Taken together, these findings suggest that UNC-45A may play a role in the physiology and pathology of the female reproductive apparatus and the central nervous system.…”

Section: Introductionmentioning

confidence: 76%

“…In the white matter, intense UNC-45A staining can be seen in cross-sections of single axons (Figure 5C), surrounded by UNC-45A-negative myeline sheath. Interestingly, a strong UNC-45A expression can also be found in the feet of the astrocytes forming the hematoencephalic barrier in the area of 13 around vessels (Figure 5B, green inset, green arrows) while the ependymocytes express UNC-45A prevalently in their cilia (Figure 5D, red asterisk), with the cytoplasm being just weakly positive. In the nerve root, the meninges (Figure 5E lower panel, black arrow) are negative for UNC-45A while a strong UNC-45A staining can be found in both, longitudinal (Figure 5F) and cross-sections (Figure 5G).…”

Section: Unc-45a Is Expressed In the Microtubule-rich Regions Of The Mouse Central Nervous System (Cns) And Mouse Nerve Rootsmentioning

confidence: 99%

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UNC-45A Is Highly Expressed in the Proliferative Cells of the Mouse Genital Tract and in the Microtubule-Rich Areas of the Mouse Nervous System

Clemente

Hoshino

Meints

et al. 2021

Cells

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UNC-45A (Protein unc-45 homolog A) is a cytoskeletal-associated protein with a dual and non-mutually exclusive role as a regulator of the actomyosin system and a Microtubule (MT)-destabilizing protein, which is overexpressed in human cancers including in ovarian cancer patients resistant to the MT-stabilizing drug paclitaxel. Mapping of UNC-45A in the mouse upper genital tract and central nervous system reveals its enrichment not only in highly proliferating and prone to remodeling cells, but also in microtubule-rich areas, of the ovaries and the nervous system, respectively. In both apparatuses, UNC-45A is also abundantly expressed in the ciliated epithelium. As regulators of actomyosin contractility and MT stability are essential for the physiopathology of the female reproductive tract and of neuronal development, our findings suggest that UNC-45A may have a role in ovarian cancer initiation and development as well as in neurodegeneration.

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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

Cited by 21 publications

References 50 publications

Roles of palmitoylation in structural long-term synaptic plasticity

Roles of palmitoylation in structural long-term synaptic plasticity

Pharmacological Modulators of Small GTPases of Rho Family in Neurodegenerative Diseases

UNC-45A Is Highly Expressed in the Proliferative Cells of the Mouse Genital Tract and in the Microtubule-Rich Areas of the Mouse Nervous System

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