scholarly journals Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

2019 ◽  
Author(s):  
Júlia Canet-Pons ◽  
Nesli-Ece Sen ◽  
Aleksandar Arsovic ◽  
Luis-Enrique Almaguer-Mederos ◽  
Melanie V. Halbach ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Molecular Mechanisms ◽  
Cholesterol Biosynthesis ◽  
Sensory Neuropathy ◽  
Lower Limbs ◽  
Spinocerebellar Ataxia Type ◽  
Motor Deficit ◽  
Mrna Levels ◽  
Polyglutamine Expansions ◽  
Cholesterol Precursor

AbstractLarge polyglutamine expansions in Ataxin-2 (ATXN2) cause multi-system nervous atrophy in Spinocerebellar Ataxia type 2 (SCA2). Intermediate size expansions carry a risk for selective motor neuron degeneration, known as Amyotrophic Lateral Sclerosis (ALS). Conversely, the depletion of ATXN2 prevents disease progression in ALS. Although ATXN2 interacts directly with RNA, and in ALS pathogenesis there is a crucial role of RNA toxicity, the affected functional pathways remain ill defined. Here, we examined an authentic SCA2 mouse model with Atxn2-CAG100-KnockIn for a first definition of molecular mechanisms in spinal cord pathology. Neurophysiology of lower limbs detected sensory neuropathy rather than motor denervation. Triple immunofluorescence demonstrated cytosolic ATXN2 aggregates sequestrating TDP43 and TIA1 from the nucleus. In immunoblots, this was accompanied by elevated CASP3, RIPK1 and PQBP1 abundance. RT-qPCR showed increase of Grn, Tlr7 and Rnaset2 mRNA versus Eif5a2, Dcp2, Uhmk1 and Kif5a decrease. These SCA2 findings overlap well with known ALS features. Similar to other ataxias and dystonias, decreased mRNA levels for Unc80, Tacr1, Gnal, Ano3, Kcna2, Elovl5 and Cdr1 contrasted with Gpnmb increase. Preterminal stage tissue showed strongly activated microglia containing ATXN2 aggregates, with parallel astrogliosis. Global transcriptome profiles from stages of incipient motor deficit versus preterminal age identified molecules with progressive downregulation, where a cluster of cholesterol biosynthesis enzymes including Dhcr24, Msmo1, Idi1 and Hmgcs1 was prominent. Gas chromatography demonstrated a massive loss of crucial cholesterol precursor metabolites. Overall, the ATXN2 protein aggregation process affects diverse subcellular compartments, in particular stress granules, endoplasmic reticulum and receptor tyrosine kinase signaling. These findings identify new targets and potential biomarkers for neuroprotective therapies.

scholarly journals Is there a right time for surgery in paraplegic patients secondary to non traumatic spinal cord compression?

2012 ◽  
Vol 10 (4) ◽  
pp. 508-511 ◽  
Author(s):  
Leonardo Giacomini ◽  
Roger Neves Mathias ◽  
Andrei Fernandes Joaquim ◽  
Mateus Dal Fabbro ◽  
Enrico Ghizoni ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Prognostic Factor ◽  
Spinal Cord Compression ◽  
Cord Compression ◽  
Lower Limbs ◽  
Motor Deficit ◽  
Indication For Surgery ◽  
Sensory Deficits ◽  
Sensory Involvement ◽  
Spinal Cord Decompression

Paraplegia is a well-defined state of complete motor deficit in lower limbs, regardless of sensory involvement. The cause of paraplegia usually guides treatment, however, some controversies remain about the time and benefits for spinal cord decompression in nontraumatic paraplegic patients, especially after 48 hours of the onset of paraplegia. The objective of this study was to evaluate the benefits of spinal cord decompression in such patients. We describe three patients with paraplegia secondary to non-traumatic spinal cord compression without sensory deficits, and who were surgically treated after more than 48 hours of the onset of symptoms. All patients, even those with paraplegia during more than 48 hours, had benefits from spinal cord decompression like recovery of gait ability. The duration of paraplegia, which influences prognosis, is not a contra-indication for surgery. The preservation of sensitivity in this group of patients should be considered as a positive prognostic factor when surgery is taken into account.

scholarly journals Cyclosporin-induced dyslipoproteinemia is associated with selective activation of SREBP-2

1999 ◽  
Vol 277 (6) ◽  
pp. E1087-E1094 ◽  
Author(s):  
Jinmei Wu ◽  
Yong Hong Zhu ◽  
Shailendra B. Patel
Keyword(s):  
Cyclosporin A ◽  
Molecular Mechanisms ◽  
Plasma Cholesterol ◽  
Regulatory Element ◽  
Cholesterol Biosynthesis ◽  
Mrna Level ◽  
Northern Analysis ◽  
Mrna Levels ◽  
Selective Activation ◽  
Vldl Triglyceride

The use of cyclosporin A has contributed greatly to the success of organ transplantation. However, cyclosporin-associated side effects of hypertension, nephrotoxicity, and dyslipoproteinemia have tempered these benefits. Cyclosporin-induced dyslipoproteinemia may be an important risk factor for the accelerated atherosclerosis observed posttransplantation. Using a mouse model, we treated Swiss-Webster mice for 6 days with a daily dose of 20 μg/g body wt of cyclosporin and observed significant elevations of plasma cholesterol, triglyceride, and apolipoprotein B (apoB) levels relative to vehicle-alone treated control animals. Measurement of the rate of secretion of very low-density lipoprotein (VLDL) by the liver in vivo showed that cyclosporin treatment led to a significant increase in the rate of hepatic VLDL triglyceride secretion. Total apoB secretion was unaffected. Northern analysis showed that cyclosporin A treatment increased the abundance of hepatic mRNA levels for a number of key genes involved in cholesterol biosynthesis relative to vehicle-alone treated animals. Two key transcriptional factors, sterol regulatory element-binding protein (SREBP)-1 and SREBP-2, also showed differential expression; SREBP-2 expression was increased at the mRNA level, and there was an increase in the active nuclear form, whereas the mRNA and the nuclear form of SREBP-1 were reduced. These results show that the molecular mechanisms by which cyclosporin causes dyslipoproteinemia may, in part, be mediated by selective activation of SREBP-2, leading to enhanced expression of lipid metabolism genes and hepatic secretion of VLDL triglyceride.

scholarly journals ALS-associated genes in SCA2 mouse spinal cord transcriptomes

2020 ◽  
Vol 29 (10) ◽  
pp. 1658-1672 ◽  
Author(s):  
Daniel R Scoles ◽  
Warunee Dansithong ◽  
Lance T Pflieger ◽  
Sharan Paul ◽  
Mandi Gandelman ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Innate Immunity ◽  
Motor Neuron ◽  
Complement System ◽  
Fatty Acid Biosynthesis ◽  
Cholesterol Biosynthesis ◽  
Cag Repeat ◽  
Spinocerebellar Ataxia Type ◽  
Als Patients ◽  
The Complement System

Abstract The spinocerebellar ataxia type 2 (SCA2) gene ATXN2 has a prominent role in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS). In addition to cerebellar ataxia, motor neuron disease is often seen in SCA2, and ATXN2 CAG repeat expansions in the long normal range increase ALS risk. Also, lowering ATXN2 expression in TDP-43 ALS mice prolongs their survival. Here we investigated the ATXN2 relationship with motor neuron dysfunction in vivo by comparing spinal cord (SC) transcriptomes reported from TDP-43 and SOD1 ALS mice and ALS patients with those from SCA2 mice. SC transcriptomes were determined using an SCA2 bacterial artificial chromosome mouse model expressing polyglutamine expanded ATXN2. SCA2 cerebellar transcriptomes were also determined, and we also investigated the modification of gene expression following treatment of SCA2 mice with an antisense oligonucleotide (ASO) lowering ATXN2 expression. Differentially expressed genes (DEGs) defined three interconnected pathways (innate immunity, fatty acid biosynthesis and cholesterol biosynthesis) in separate modules identified by weighted gene co-expression network analysis. Other key pathways included the complement system and lysosome/phagosome pathways. Of all DEGs in SC, 12.6% were also dysregulated in the cerebellum. Treatment of mice with an ATXN2 ASO also modified innate immunity, the complement system and lysosome/phagosome pathways. This study provides new insights into the underlying molecular basis of SCA2 SC phenotypes and demonstrates annotated pathways shared with TDP-43 and SOD1 ALS mice and ALS patients. It also emphasizes the importance of ATXN2 in motor neuron degeneration and confirms ATXN2 as a therapeutic target.

scholarly journals Protective Effect of Psoralea corylifolia L. Seed Extract against Palmitate-Induced Neuronal Apoptosis in PC12 Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Yunkyoung Lee ◽  
Hee-Sook Jun ◽  
Yoon Sin Oh
Keyword(s):  
Pc12 Cells ◽  
Molecular Mechanisms ◽  
Neuronal Cell ◽  
Marker Genes ◽  
Heme Oxygenase 1 ◽  
Mrna Levels ◽  
Protective Effects ◽  
Psoralea Corylifolia ◽  
Antioxidant Genes ◽  
Bax Protein

The extract of Psoralea corylifolia seeds (PCE) has been widely used as a herbal medicine because of its beneficial effect on human health. In this study, we investigated the protective effects and molecular mechanisms of PCE on palmitate- (PA-) induced toxicity in PC12 cells, a neuron-like cell line. PCE significantly increased cell viability in PA-treated PC12 cells and showed antiapoptotic effects, as evidenced by decreased expression of cleaved caspase-3, cleaved poly(ADP-ribose) polymerase, and bax protein as well as increased expression of bcl-2 protein. In addition, PCE treatment reduced PA-induced reactive oxygen species production and upregulated mRNA levels of antioxidant genes such as nuclear factor (erythroid-derived 2)-like 2 and heme oxygenase 1. Moreover, PCE treatment recovered the expression of autophagy marker genes such as beclin-1 and p62, which was decreased by PA treatment. Treatment with isopsoralen, one of the major components of PCE extract, also recovered the expression of autophagy marker genes and reduced PA-induced apoptosis. In conclusion, PCE exerts protective effects against lipotoxicity via its antioxidant function, and this effect is mediated by activation of autophagy. PCE might be a potential pharmacological agent to protect against neuronal cell injury caused by oxidative stress or lipotoxicity.

scholarly journals Molecular Mechanisms of ZC3H12C/Reg-3 Biological Activity and Its Involvement in Psoriasis Pathology

2021 ◽  
Vol 22 (14) ◽  
pp. 7311
Author(s):  
Mateusz Wawro ◽  
Jakub Kochan ◽  
Weronika Sowinska ◽  
Aleksandra Solecka ◽  
Karolina Wawro ◽  
...  
Keyword(s):  
Family Member ◽  
Cellular Localization ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Association Studies ◽  
Psoriasis Patient ◽  
Genome Wide Association Studies ◽  
Mrna Levels ◽  
Transcript Levels

The members of the ZC3H12/MCPIP/Regnase family of RNases have emerged as important regulators of inflammation. In contrast to Regnase-1, -2 and -4, a thorough characterization of Regnase-3 (Reg-3) has not yet been explored. Here we demonstrate that Reg-3 differs from other family members in terms of NYN/PIN domain features, cellular localization pattern and substrate specificity. Together with Reg-1, the most comprehensively characterized family member, Reg-3 shared IL-6, IER-3 and Reg-1 mRNAs, but not IL-1β mRNA, as substrates. In addition, Reg-3 was found to be the only family member which regulates transcript levels of TNF, a cytokine implicated in chronic inflammatory diseases including psoriasis. Previous meta-analysis of genome-wide association studies revealed Reg-3 to be among new psoriasis susceptibility loci. Here we demonstrate that Reg-3 transcript levels are increased in psoriasis patient skin tissue and in an experimental model of psoriasis, supporting the immunomodulatory role of Reg-3 in psoriasis, possibly through degradation of mRNA for TNF and other factors such as Reg-1. On the other hand, Reg-1 was found to destabilize Reg-3 transcripts, suggesting reciprocal regulation between Reg-3 and Reg-1 in the skin. We found that either Reg-1 or Reg-3 were expressed in human keratinocytes in vitro. However, in contrast to robustly upregulated Reg-1 mRNA levels, Reg-3 expression was not affected in the epidermis of psoriasis patients. Taken together, these data suggest that epidermal levels of Reg-3 are negatively regulated by Reg-1 in psoriasis, and that Reg-1 and Reg-3 are both involved in psoriasis pathophysiology through controlling, at least in part different transcripts.

scholarly journals Acute-onset paraplegia as an unexpected complication under general anesthesia in supine position during abdominal endovascular aneurysm repair: a case report

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Atsushi Morio ◽  
Hirotsugu Miyoshi ◽  
Noboru Saeki ◽  
Yukari Toyota ◽  
Yasuo M. Tsutsumi
Keyword(s):  
Spinal Cord ◽  
General Anesthesia ◽  
Supine Position ◽  
Spinal Cord Ischemia ◽  
Endovascular Aneurysm Repair ◽  
Acute Onset ◽  
Lower Limbs ◽  
Canal Stenosis ◽  
Cord Injury ◽  
Aneurysm Repair

Abstract Background Acute onset paraplegia after endovascular aneurysm repair (EVAR) is a rare but well-known complication. We here show a 79-year-old woman with paraplegia caused by static and dynamic spinal cord insult not by ischemia after EVAR. Case presentation The patient underwent EVAR for abdominal aortic aneurism under general anesthesia in the supine position. She had a medical history of lumbar canal stenosis. After the surgery, we recognized severe paraplegia and sensory disorder of lower limbs. Although the possibility of spinal cord ischemia was considered at that time, postoperative magnetic resonance imaging (MRI) revealed burst fracture of vertebra and compressed spinal cord. Conclusions Patients with spinal canal stenosis can cause extrinsic spinal cord injury even with weak external forces. Thus, even after EVAR, it is important to consider extrinsic factors as the cause of paraplegia.

How to Do It: Microsurgical DREZotomy for Pain After Brachial Plexus Injury: 2-Dimensional Operative Video

2021 ◽  
Author(s):  
Manon Duraffourg ◽  
Andrei Brinzeu ◽  
Marc Sindou
Keyword(s):  
Spinal Cord ◽  
Pain Relief ◽  
Brachial Plexus ◽  
Dorsal Horn ◽  
Brachial Plexus Injury ◽  
Dorsal Column ◽  
Motor Deficit ◽  
Complete Disappearance ◽  
Burning Pain ◽  
Root Entry Zone

Abstract More than three-quarters of victims of brachial plexus injury suffer from refractory neuropathic pain.1-6 Main putative mechanism is paroxysmal hyperactivity in the dorsal horn neurons at the dorsal root entry zone (DREZ) as demonstrated by microelectrode recordings in animal models7 and patients.8 Pain relief can be achieved by lesioning the responsible neurons in the spinal cord segments with avulsed rootlets.9,10  This video illustrates the technique for microsurgical DREZotomy.11,12 A C3-C7 hemilaminectomy is performed to access the C4-Th1 medullary segments. After opening the dura and arachnoid, and freeing the cord from arachnoid adhesions, the dorsolateral sulcus is identified. Identification can be difficult when the spinal cord is distorted and/or has a loss of substance. The dorsolateral sulcus is then opened with a microknife, so that microcoagulations are performed: 4 mm deep, at 35° angle in the axis of the dorsal horn, every millimeter in a dotted fashion along the avulsed segments. Care should be taken not to damage the corticospinal tract, laterally, and the dorsal column, medially.  The patient consents to the procedure. In the presented case, surgery led to complete disappearance of the paroxysmal pain and reduced the background of burning pain to a bearable level without the need of opioid medication. There was no motor deficit or ataxia in the ipsilateral lower limb postoperatively. According to Kaplan-Meier analysis at 10 yr follow-up, in our overall series, microsurgical DREZotomy achieved total pain relief without any medication in 60% of patients, and in 85% without the need for opioids.10,13-15  Microelectrode recording at 1:26 reproduced from Guenot et al7 with permission from JNSPG.

scholarly journals Targeting fibroblast growth factor receptors to combat aggressive ependymoma

2021 ◽  
Author(s):  
Daniela Lötsch ◽  
Dominik Kirchhofer ◽  
Bernhard Englinger ◽  
Li Jiang ◽  
Konstantin Okonechnikov ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Molecular Mechanisms ◽  
Radial Glia ◽  
Growth Factor Receptors ◽  
Dominant Negative ◽  
Mrna Levels ◽  
Fibroblast Growth ◽  
Cell Models ◽  
Fibroblast Growth Factor Receptors

AbstractEpendymomas (EPN) are central nervous system tumors comprising both aggressive and more benign molecular subtypes. However, therapy of the high-risk subtypes posterior fossa group A (PF-A) and supratentorial RELA-fusion positive (ST-RELA) is limited to gross total resection and radiotherapy, as effective systemic treatment concepts are still lacking. We have recently described fibroblast growth factor receptors 1 and 3 (FGFR1/FGFR3) as oncogenic drivers of EPN. However, the underlying molecular mechanisms and their potential as therapeutic targets have not yet been investigated in detail. Making use of transcriptomic data across 467 EPN tissues, we found that FGFR1 and FGFR3 were both widely expressed across all molecular groups. FGFR3 mRNA levels were enriched in ST-RELA showing the highest expression among EPN as well as other brain tumors. We further identified high expression levels of fibroblast growth factor 1 and 2 (FGF1, FGF2) across all EPN subtypes while FGF9 was elevated in ST-EPN. Interrogation of our EPN single-cell RNA-sequencing data revealed that FGFR3 was further enriched in cycling and progenitor-like cell populations. Corroboratively, we found FGFR3 to be predominantly expressed in radial glia cells in both mouse embryonal and human brain datasets. Moreover, we detected alternative splicing of the FGFR1/3-IIIc variant, which is known to enhance ligand affinity and FGFR signaling. Dominant-negative interruption of FGFR1/3 activation in PF-A and ST-RELA cell models demonstrated inhibition of key oncogenic pathways leading to reduced cell growth and stem cell characteristics. To explore the feasibility of therapeutically targeting FGFR, we tested a panel of FGFR inhibitors in 12 patient-derived EPN cell models revealing sensitivity in the low-micromolar to nano-molar range. Finally, we gain the first clinical evidence for the activity of the FGFR inhibitor nintedanib in the treatment of a patient with recurrent ST-RELA. Together, these preclinical and clinical data suggest FGFR inhibition as a novel and feasible approach to combat aggressive EPN.

scholarly journals Spinal Cord Injury Increases Pro-inflammatory Cytokine Expression in Kidney at Acute and Sub-chronic Stages

Inflammation ◽  
2021 ◽  
Author(s):  
Shangrila Parvin ◽  
Clintoria R. Williams ◽  
Simone A. Jarrett ◽  
Sandra M. Garraway
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Inflammatory Response ◽  
Inflammatory Cytokine ◽  
Cardiovascular Health ◽  
Mrna Levels ◽  
Post Injury ◽  
Cord Injury ◽  
And Function ◽  
The Impact

Abstract— Accumulating evidence supports that spinal cord injury (SCI) produces robust inflammatory plasticity. We previously showed that the pro-inflammatory cytokine tumor necrosis factor (TNF)α is increased in the spinal cord after SCI. SCI also induces a systemic inflammatory response that can impact peripheral organ functions. The kidney plays an important role in maintaining cardiovascular health. However, SCI-induced inflammatory response in the kidney and the subsequent effect on renal function have not been well characterized. This study investigated the impact of high and low thoracic (T) SCI on C-fos, TNFα, interleukin (IL)-1β, and IL-6 expression in the kidney at acute and sub-chronic timepoints. Adult C57BL/6 mice received a moderate contusion SCI or sham procedures at T4 or T10. Uninjured mice served as naïve controls. mRNA levels of the proinflammatory cytokines IL-1β, IL-6, TNFα, and C-fos, and TNFα and C-fos protein expression were assessed in the kidney and spinal cord 1 day and 14 days post-injury. The mRNA levels of all targets were robustly increased in the kidney and spinal cord, 1 day after both injuries. Whereas IL-6 and TNFα remained elevated in the spinal cord at 14 days after SCI, C-fos, IL-6, and TNFα levels were sustained in the kidney only after T10 SCI. TNFα protein was significantly upregulated in the kidney 1 day after both T4 and T10 SCI. Overall, these results clearly demonstrate that SCI induces robust systemic inflammation that extends to the kidney. Hence, the presence of renal inflammation can substantially impact renal pathophysiology and function after SCI.

scholarly journals Statin use is associated with reduced motor recovery after spinal cord injury

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Erin M. Triplet ◽  
Isobel A. Scarisbrick
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Motor Recovery ◽  
Motor Deficit ◽  
Historical Cohort ◽  
Cholesterol Lowering ◽  
Severity Of Injury ◽  
Cord Injury ◽  
The Impact ◽  
Statin Use

Abstract Study design We completed retrospective analysis of statin use in individuals with neurologically significant spinal cord injury in a historical cohort study. Objective Our objective was to establish the prevalence of cholesterol-lowering agent use following spinal cord injury (SCI) and to determine the impact on recovery of motor function. Setting Patients enrolled in the Rochester Epidemiology Project in Olmsted County, Minnesota, USA from 2005 to 2018 were included in analysis. Methods Exclusion criteria: age <18, comorbid neurological disease, prior neurological deficit, nontraumatic injury, survival <1 year, or lack of motor deficit. Demographics and cholesterol-lowering agent use in 83 individuals meeting all criteria were recorded. A total of 68/83 individuals were then assessed for change in function over the first 2 months after injury using the ISNCSCI motor subscore. Statistical comparison between control and statin groups was done by two-sided Chi-squared test or two-tailed Student’s t test. Generalized regression was performed to assess associations between independent variables and functional outcome. Results 30% of individuals with SCI had a prescription for a cholesterol-lowering agent. No significant differences were observed in severity of injury or demographic composition between groups. The change in motor subscore was reduced in the statin group compared to controls (p = 0.03, Mann–Whitney). Both severity of injury and statin were significant predictors of reduced motor recovery (p = 0.001, and p = 0.04, respectively). Conclusions Both severity of SCI and statins were significant predictors of reduced motor recovery. Additional investigation is needed to address potential impact of statin-therapy in the context of CNS injury and repair.

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