Pharmacological inhibition of spinal cord injury-stimulated ribosomal biogenesis does not affect locomotor outcome

Kilańczyk, Ewa; Andres, Kariena R.; Hallgren, Justin; Ohri, Sujata Saraswat; Laiho, Marikki; Whittemore, Scott R.; Hetman, Michał

doi:10.1016/j.neulet.2017.02.011

Cited by 6 publications

(6 citation statements)

References 29 publications

(51 reference statements)

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“…The function of ribosomes is to synthesize amino acids into protein polypeptide chains according to the instructions of mRNA. 28 Here, we can find ribonucleoprotein complex biogenesis, ribosome biogenesis, preribosome, rRNA processing, nucleolus RNA processing, and rRNA metabolic process are all related to ribosome. This is consistent with our previous report.…”

Section: Discussionmentioning

confidence: 92%

“…By combining those signal pathways inhibited by M2 cells, we found that some pathways have been reported to be involved in SCI. For example, CAMs, 42,43 antigen processing and presentation, 28,44 phagosome, 45 natural killer cell-mediated cytotoxicity, 46,47 endocytosis, 48,49 proteasome, 50,51 and Toll-like receptor signaling pathway. 52,53 These are related to the pathological mechanism of SCI.…”

Section: Discussionmentioning

confidence: 99%

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Effect of M2 macrophage adoptive transfer on transcriptome profile of injured spinal cords in rats

Chen

Yan

Duan

et al. 2019

Exp Biol Med (Maywood)

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The previous studies showed that alternatively activated anti-inflammatory macrophage (M2) adoptive immunity can improve the proportion of local M2 cells and play the neuroprotective effect after spinal cord injury (SCI). Its molecular mechanism is not yet very clear. Therefore, this study aims to analyze the effect of the M2 adoptive transfer on the local expression of gene transcription. Sprague-Dawley (SD) rats were used for culture of macrophages and establishment of SCI models. After SCI, the polarized M2 macrophages were transferred to the injured rats by tail vein injection. Seven days after operation, the differentially expressed genes (DEGs) in the spinal cords were analyzed by RNA-sequencing (RNA-Seq). Then, the functional enrichment analysis and pathways were performed by using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), respectively. RNA-Seq showed that M2 adoptive immunity can down-regulate many well-studied gene expressions associated with signaling pathways of inflammatory, such as antigen processing and presentation, phagosome, cell adhesion molecules, natural killer cell-mediated cytotoxicity, endocytosis, proteasome, and Toll-like receptor signaling pathway. These may explain the mechanism of our previous adoptive immunization of M2 cells to provide neuroprotection for SCI. In addition, a novel pathway, retinoic acid-inducible gene-1 (RIG-I)-like receptor signaling pathway was found to be involved in the pathological process of SCI and the response to M2 adoptive immunity as well. This will provide a new explanation for the pathological mechanism of SCI and a new theoretical and experimental basis for its clinical treatment. The raw Illumina data are available at http://www.ncbi.nlm.nih.gov/sra (accession number PRJNA517238). Impact statement This research aimed to analyze the effect of M2 macrophage adoptive transfer on the local expression of gene transcription after SCI by RNA-Seq. The results showed that M2 adoptive immunity can down-regulate many well-studied gene expressions associated with signaling pathways of inflammatory. These may explain the mechanism of our previous adoptive immunization of M2 cells to provide neuroprotection for SCI. In addition, a novel pathway, RIG-I-like receptor signaling pathway was also found to involve in the pathological process of SCI and the response to M2 adoptive immunity. This will provide a new explanation for the pathological mechanism of SCI and a new theoretical and experimental basis for its clinical treatment.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Effect of M2 macrophage adoptive transfer on transcriptome profile of injured spinal cords in rats

Chen

Yan

Duan

et al. 2019

Exp Biol Med (Maywood)

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“…Therefore, future studies could address that issue in such clinically-relevant models of epileptogenesis as post-SE TLE or tuberous sclerosis-like epilepsy in Tsc1 KO mice [44,64]. Adequate experimental approaches may include neuroprogenitor cell- and/or astrocyte-selective KO of Tif1a and/or pharmacological treatment with CNS-permeable anti-cancer Pol1 inhibitors such as the non-toxic BMH-21 [68]. …”

Section: Discussionmentioning

confidence: 99%

RNA Polymerase 1 Is Transiently Regulated by Seizures and Plays a Role in a Pharmacological Kindling Model of Epilepsy

et al. 2018

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Ribosome biogenesis, including the RNA polymerase 1 (Pol1)-mediated transcription of rRNA, is regulated by the pro-epileptogenic mTOR pathway. Therefore, hippocampal Pol1 activity was examined in mouse models of epilepsy including kainic acid- and pilocarpine-induced status epilepticus (SE) as well as a single seizure in response to pentylenetetrazole (PTZ). Elevated 47S pre-rRNA levels were present acutely after induction of SE suggesting activation of Pol1. Conversely, after a single seizure, 47S pre-rRNA was transiently downregulated with increased levels of unprocessed 18S rRNA precursors in the cornu Ammonis (CA) region. At least in the dentate gyrus (DG), the pilocarpine SE-mediated transient activation of Pol1 did not translate into long-term changes of pre-rRNA levels or total ribosome content. Unaltered hippocampal ribosome content was also found after a 20-day PTZ kindling paradigm with increasing pro-convulsive effects of low dose PTZ that was injected every other day. However, after selectively deleting the essential Pol1 co-activator, transcription initiation factor-1A (Tif1a/Rrn3) from excitatory neurons, PTZ kindling was impaired while DG total ribosome content was moderately reduced and no major neurodegeneration was observed throughout the hippocampus. Therefore, Pol1 activity of excitatory neurons is required for PTZ kindling. As seizures affect ribosome biogenesis without long-term effects on the total ribosome content, such a requirement may be associated with a need to produce specialized ribosomes that promote pro-epileptic plasticity.

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“…BMH-21 is a planar heterocyclic small molecule DNA intercalator that binds strongly to GC-rich DNA sequences, ultimately inhibiting Pol I, blocking transcription and disrupting nucleolar structure [45]. BMH-21 penetrates the CNS and has been used in murine preclinical studies of spinal cord injury [46], but is not being used in clinical studies at present due to deleterious off-target effects.…”

Section: Pol I Inhibitorsmentioning

confidence: 99%

Polymerase I as a Target for Treating Neurodegenerative Disorders

LeDoux

2024

Preprint

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Polymerase I (Pol I) is at the epicenter of ribosomal RNA (rRNA) synthesis. Pol I is a target for treatment of cancer. Given the many cellular commonalities between cancer and neurodegeneration (i.e., different faces of the same coin) it seems rational to consider targeting of Pol I or, more generally, rRNA synthesis for treatment of disorders associated with the death of terminally differentiated neurons. Principally, ribosomes synthesize proteins and, accordingly, Pol I can be considered the starting point for protein synthesis. Given that cellular accumulation of abnormal proteins such as α-synuclein and tau is an essential feature of neurodegenerative disorders such as Parkinson disease and fronto-temporal dementia, reduction of protein production is now considered as a viable target for treatment of these and closely related neurodegenerative disorders. Abnormalities in polymerase I activity and rRNA production may also be associated with nuclear and nucleolar stress, DNA damage, and childhood onset neuronal death as is the case for the UBTF E210K neuroregression syndrome. Moreover, restraining the activity of Pol I may be a viable strategy to slow aging. Before starting down the road of Pol I inhibition for treating non-cancerous disorders of the nervous system, many questions must be answered. First, how much Pol I inhibition can neurons tolerate and for how long? Should inhibition of Pol I be continuous or pulsed? Will cells compensate for Pol I inhibition by upregulating the number of active rDNAs? At present, we have no effective and safe disease modulatory treatments for Alzheimer disease, α-synucleinopathies, or tauopathies, and novel therapeutic targets and approaches must be explored.

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Pharmacological inhibition of spinal cord injury-stimulated ribosomal biogenesis does not affect locomotor outcome

Cited by 6 publications

References 29 publications

Effect of M2 macrophage adoptive transfer on transcriptome profile of injured spinal cords in rats

Effect of M2 macrophage adoptive transfer on transcriptome profile of injured spinal cords in rats

RNA Polymerase 1 Is Transiently Regulated by Seizures and Plays a Role in a Pharmacological Kindling Model of Epilepsy

Polymerase I as a Target for Treating Neurodegenerative Disorders

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