Pharmacological Modulators of Small GTPases of Rho Family in Neurodegenerative Diseases

Guiler, William; Koehler, Addison; Boykin, Christi; Lü, Qun

doi:10.3389/fncel.2021.661612

Cited by 32 publications

(20 citation statements)

References 174 publications

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“…For the sham operation, the left sciatic nerve was only exposed without crush or transection. All animals received analgesic treatment with buprenorphine (0.05 mg/kg) [ 24 , 25 ] injection twice a day until 3 days post the surgery. Based on the protocols of power calculation for group size [ 26 , 27 ] and the data of pre-experiment, 6 mice/group were used for each test.…”

Section: Methodsmentioning

confidence: 99%

Macrophage-specific RhoA knockout delays Wallerian degeneration after peripheral nerve injury in mice

Wen

et al. 2021

J Neuroinflammation

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Background Plenty of macrophages are recruited to the injured nerve to play key roles in the immunoreaction and engulf the debris of degenerated axons and myelin during Wallerian degeneration, thus creating a conducive microenvironment for nerve regeneration. Recently, drugs targeting the RhoA pathway have been widely used to promote peripheral axonal regeneration. However, the role of RhoA in macrophage during Wallerian degeneration and nerve regeneration after peripheral nerve injury is still unknown. Herein, we come up with the hypothesis that RhoA might influence Wallerian degeneration and nerve regeneration by affecting the migration and phagocytosis of macrophages after peripheral nerve injury. Methods Immunohistochemistry, Western blotting, H&E staining, and electrophysiology were performed to access the Wallerian degeneration and axonal regeneration after sciatic nerve transection and crush injury in the LyzCre+/−; RhoAflox/flox (cKO) mice or Lyz2Cre+/− (Cre) mice, regardless of sex. Macrophages’ migration and phagocytosis were detected in the injured nerves and the cultured macrophages. Moreover, the expression and potential roles of ROCK and MLCK were also evaluated in the cultured macrophages. Results 1. RhoA was specifically knocked out in macrophages of the cKO mice; 2. The segmentation of axons and myelin, the axonal regeneration, and nerve conduction in the injured nerve were significantly impeded while the myoatrophy was more severe in the cKO mice compared with those in Cre mice; 3. RhoA knockout attenuated the migration and phagocytosis of macrophages in vivo and in vitro; 4. ROCK and MLCK were downregulated in the cKO macrophages while inhibition of ROCK and MLCK could weaken the migration and phagocytosis of macrophages. Conclusions Our findings suggest that RhoA depletion in macrophages exerts a detrimental effect on Wallerian degeneration and nerve regeneration, which is most likely due to the impaired migration and phagocytosis of macrophages resulted from disrupted RhoA/ROCK/MLCK pathway. Since previous research has proved RhoA inhibition in neurons was favoring for axonal regeneration, the present study reminds us of that the cellular specificity of RhoA-targeted drugs is needed to be considered in the future application for treating peripheral nerve injury.

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Section: Methodsmentioning

confidence: 99%

Macrophage-specific RhoA knockout delays Wallerian degeneration after peripheral nerve injury in mice

Wen

et al. 2021

J Neuroinflammation

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“…ROCK1 is control group, ### p < 0.001 vs. model group mainly distributed in peripheral tissues such as the heart and skeletal muscle, and ROCK2 is mainly distributed in the nervous system (Yan et al, 2019). After ROCK is activated by Rho, the actin-binding protein cofilin is abnormally phosphorylate and loses the function of cutting actin (Guiler et al, 2021). ROCKs have more than 30 downstream substrates, the most classic ones include Tau, Limk1, and p-cofilin, etc (Shi & Wei, 2022).…”

Section: Discussionsmentioning

confidence: 99%

Acrolein, an endogenous aldehyde induces synaptic dysfunction in vitro and in vivo: Involvement of RhoA/ROCK2 pathway

Zhu

Wang

et al. 2022

Aging Cell

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Acrolein, an unsaturated aldehyde, is increased in the brain of Alzheimer's disease (AD) patients and identified as a potential inducer of sporadic AD. Synaptic dysfunction, as a typical pathological change occurring in the early stage of AD, is most closely associated with the severity of dementia. However, there remains a lack of clarity on the mechanisms of acrolein inducing AD‐like pathology and synaptic impairment. In this study, acrolein‐treated primary cultured neurons and mice were applied to investigate the effects of acrolein on cognitive impairment and synaptic dysfunction and their signaling mechanisms. In vitro, ROCK inhibitors, Fasudil, and Y27632, could attenuate the axon ruptures and synaptic impairment caused by acrolein. Meanwhile, RNA‐seq distinct differentially expressed genes in acrolein models and initially linked activated RhoA/Rho‐kinase2 (ROCK2) to acrolein‐induced synaptic dysfunction, which could regulate neuronal cytoskeleton and neurite. The Morris water maze test and in vivo field excitatory postsynaptic potential (fEPSP) were performed to evaluate spatial memory and long‐term potential (LTP), respectively. Acrolein induced cognitive impairment and attenuated LTP. Furthermore, the protein level of Synapsin 1 and postsynaptic density 95 (PSD95) and dendritic spines density were also decreased in acrolein‐exposed mice. These changes were improved by ROCK2 inhibitor Fasudil or in ROCK2 +/− mice. Together, our findings suggest that RhoA/ROCK2 signaling pathway plays a critical role in acrolein‐induced synaptic damage and cognitive dysfunction, suggesting inhibition of ROCK2 should benefit to the early AD.

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“…Relatively cluster enriched genes that showed large differences between MNPQ and control included Dusp3, Pianp (neurons), Ppp1r3g, Tagln3 (astrocytes) and Glul, Bsg (oligodendrocytes). Some had known links to PD, including Acp2, Rac1, Sgta (neurons) and Cntfr, Fabp5 (astrocytes) (Ashtari et al, 2016; Guiler et al, 2021; Kubota et al, 2021; Pöyhönen et al, 2019; Wang et al, 2021).…”

Section: Resultsmentioning

confidence: 99%

Single cell analysis of gene expression in the substantia nigra pars compacta of a pesticide-induced mouse model of Parkinson’s disease

Ah¹,

Lee²,

Smith³

2022

Preprint

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Exposure to pesticides in humans increases the risk of Parkinson's disease (PD), but the mechanisms remain poorly understood. To elucidate these pathways, we dosed C57BL/6J mice with a combination of the pesticides maneb and paraquat (MNPQ). Behavioral analysis revealed motor deficits consistent with PD. Single cell RNA sequencing of substantia nigra pars compacta revealed both cell-type specific genes and genes expressed differentially between pesticide and control, including Fam241b, Emx2os, Bivm, Gm1439, Prdm15 and Rai2. Neurons had the largest number of significant differentially expressed genes, but comparable numbers were found in astrocytes and less so in oligodendrocytes. In addition, network analysis revealed enrichment in functions related to the extracellular matrix. These findings emphasize the importance of support cells in pesticide-induced PD and refocus our attention away from neurons as the sole agent of this disorder.

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Pharmacological Modulators of Small GTPases of Rho Family in Neurodegenerative Diseases

Cited by 32 publications

References 174 publications

Macrophage-specific RhoA knockout delays Wallerian degeneration after peripheral nerve injury in mice

Macrophage-specific RhoA knockout delays Wallerian degeneration after peripheral nerve injury in mice

Acrolein, an endogenous aldehyde induces synaptic dysfunction in vitro and in vivo: Involvement of RhoA/ROCK2 pathway

Single cell analysis of gene expression in the substantia nigra pars compacta of a pesticide-induced mouse model of Parkinson’s disease

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