Peroxisome biogenesis deficiency attenuates the BDNF-TrkB pathway-mediated development of the cerebellum

Peroxisome biogenesis disorders (PBDs) manifest as neurological deficits in the central nervous system, including neuronal migration defects and abnormal cerebellum development. However, the mechanisms underlying pathogenesis remain enigmatic. Here, to investigate how peroxisome deficiency causes neurological defects of PBDs, we established a new PBD model mouse defective in peroxisome assembly factor Pex14p, termed Pex14ΔC/ΔC mouse. Pex14ΔC/ΔC mouse manifests a severe symptom such as disorganization of cortical laminar structure and dies shortly after birth, although peroxisomal biogenesis and metabolism are partially defective. The Pex14ΔC/ΔC mouse also shows malformation of the cerebellum including the impaired dendritic development of Purkinje cells. Moreover, extracellular signal-regulated kinase and AKT signaling are attenuated in this mutant mouse by an elevated level of brain-derived neurotrophic factor (BDNF) together with the enhanced expression of TrkB-T1, a dominant-negative isoform of the BDNF receptor. Our results suggest that dysregulation of the BDNF-TrkB pathway, an essential signaling for cerebellar morphogenesis, gives rise to the pathogenesis of the cerebellum in PBDs.

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Leptin and Notch Signaling Cooperate in Sustaining Glioblastoma Multiforme Progression

Biomolecules ◽

10.3390/biom10060886 ◽

2020 ◽

Vol 10 (6) ◽

pp. 886

Author(s):

Salvatore Panza ◽

Umberto Russo ◽

Francesca Giordano ◽

Antonella Leggio ◽

Ines Barone ◽

...

Keyword(s):

Glioblastoma Multiforme ◽

Notch Signaling ◽

Dominant Negative ◽

Biologically Active ◽

Gamma Secretase ◽

Leptin Receptors ◽

Downstream Effectors ◽

Enhanced Expression ◽

Forming Efficiency ◽

The Central Nervous System

Glioblastoma multiforme (GBM) is the most malignant form of glioma, which represents one of the commonly occurring tumors of the central nervous system. Despite the continuous development of new clinical therapies against this malignancy, it still remains a deadly disease with very poor prognosis. Here, we demonstrated the existence of a biologically active interaction between leptin and Notch signaling pathways that sustains GBM development and progression. We found that the expression of leptin and its receptors was significantly higher in human glioblastoma cells, U-87 MG and T98G, than in a normal human glial cell line, SVG p12, and that activation of leptin signaling induced growth and motility in GBM cells. Interestingly, flow cytometry and real-time RT-PCR assays revealed that GBM cells, grown as neurospheres, displayed stem cell-like properties (CD133+) along with an enhanced expression of leptin receptors. Leptin treatment significantly increased the neurosphere forming efficiency, self-renewal capacity, and mRNA expression levels of the stemness markers CD133, Nestin, SOX2, and GFAP. Mechanistically, we evidenced a leptin-mediated upregulation of Notch 1 receptor and the activation of its downstream effectors and target molecules. Leptin-induced effects on U-87 MG and T98G cells were abrogated by the selective leptin antagonist, the peptide LDFI (Leu-Asp-Phe-Ile), as well as by the specific Notch signaling inhibitor, GSI (Gamma Secretase Inhibitor) and in the presence of a dominant-negative of mastermind-like-1. Overall, these findings demonstrate, for the first time, a functional interaction between leptin and Notch signaling in GBM, highlighting leptin/Notch crosstalk as a potential novel therapeutic target for GBM treatment.

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Targeted Deletion of the PEX2 Peroxisome Assembly Gene in Mice Provides a Model for Zellweger Syndrome, a Human Neuronal Migration Disorder

The Journal of Cell Biology ◽

10.1083/jcb.139.5.1293 ◽

1997 ◽

Vol 139 (5) ◽

pp. 1293-1305 ◽

Cited By ~ 108

Author(s):

Phyllis L. Faust ◽

Mary E. Hatten

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Neuronal Migration ◽

Zellweger Syndrome ◽

Peroxisomal Biogenesis ◽

Migration Disorder ◽

Assembly Factor ◽

The Central Nervous System ◽

Deficient Mice ◽

Peroxisomal Function

Zellweger syndrome is a peroxisomal biogenesis disorder that results in abnormal neuronal migration in the central nervous system and severe neurologic dysfunction. The pathogenesis of the multiple severe anomalies associated with the disorders of peroxisome biogenesis remains unknown. To study the relationship between lack of peroxisomal function and organ dysfunction, the PEX2 peroxisome assembly gene (formerly peroxisome assembly factor-1) was disrupted by gene targeting. Homozygous PEX2-deficient mice survive in utero but die several hours after birth. The mutant animals do not feed and are hypoactive and markedly hypotonic. The PEX2-deficient mice lack normal peroxisomes but do assemble empty peroxisome membrane ghosts. They display abnormal peroxisomal biochemical parameters, including accumulations of very long chain fatty acids in plasma and deficient erythrocyte plasmalogens. Abnormal lipid storage is evident in the adrenal cortex, with characteristic lamellar–lipid inclusions. In the central nervous system of newborn mutant mice there is disordered lamination in the cerebral cortex and an increased cell density in the underlying white matter, indicating an abnormality of neuronal migration. These findings demonstrate that mice with a PEX2 gene deletion have a peroxisomal disorder and provide an important model to study the role of peroxisomal function in the pathogenesis of this human disease.

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AAV-mediated inhibition of ULK1 promotes axonal regeneration in the central nervous system in vitro and in vivo

Cell Death and Disease ◽

10.1038/s41419-021-03503-3 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Vinicius Toledo Ribas ◽

Björn Friedhelm Vahsen ◽

Lars Tatenhorst ◽

Veronica Estrada ◽

Vivian Dambeck ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Axonal Regeneration ◽

Dominant Negative ◽

Neurological Deficits ◽

Nerve Lesion ◽

Cord Injury ◽

The Central Nervous System

AbstractAxonal damage is an early step in traumatic and neurodegenerative disorders of the central nervous system (CNS). Damaged axons are not able to regenerate sufficiently in the adult mammalian CNS, leading to permanent neurological deficits. Recently, we showed that inhibition of the autophagic protein ULK1 promotes neuroprotection in different models of neurodegeneration. Moreover, we demonstrated previously that axonal protection improves regeneration of lesioned axons. However, whether axonal protection mediated by ULK1 inhibition could also improve axonal regeneration is unknown. Here, we used an adeno-associated viral (AAV) vector to express a dominant-negative form of ULK1 (AAV.ULK1.DN) and investigated its effects on axonal regeneration in the CNS. We show that AAV.ULK1.DN fosters axonal regeneration and enhances neurite outgrowth in vitro. In addition, AAV.ULK1.DN increases neuronal survival and enhances axonal regeneration after optic nerve lesion, and promotes long-term axonal protection after spinal cord injury (SCI) in vivo. Interestingly, AAV.ULK1.DN also increases serotonergic and dopaminergic axon sprouting after SCI. Mechanistically, AAV.ULK1.DN leads to increased ERK1 activation and reduced expression of RhoA and ROCK2. Our findings outline ULK1 as a key regulator of axonal degeneration and regeneration, and define ULK1 as a promising target to promote neuroprotection and regeneration in the CNS.

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Amiloride Alleviates Neurological Deficits Following Transient Global Ischemia and Engagement of Central IL-6 and TNF-α Signal

Current Molecular Medicine ◽

10.2174/1566524019666190704100444 ◽

2019 ◽

Vol 19 (8) ◽

pp. 597-604

Author(s):

Li Pang ◽

Shouqin Ji ◽

Jihong Xing

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Caspase 3 ◽

Global Ischemia ◽

Neurological Deficits ◽

Global Cerebral Ischemia ◽

Caspase 9 ◽

Tnf Α ◽

The Central Nervous System ◽

Transient Global Ischemia

Background: Central pro-inflammatory cytokine (PIC) signal is involved in neurological deficits after transient global ischemia induced by cardiac arrest (CA). The present study was to examine if blocking acid sensing ion channels (ASICs) using amiloride in the Central Nervous System can alleviate neurological deficits after the induction of CA and further examine the participation of PIC signal in the hippocampus for the effects of amiloride. Methods: CA was induced by asphyxia and then cardiopulmonary resuscitation was performed in rats. Western blot analysis and ELISA were used to determine the protein expression of ASIC subunit ASIC1 in the hippocampus, and the levels of PICs. As noted, it is unlikely that this procedure is clinically used although amiloride and other pharmacological agents were given into the brain in this study. Results: CA increased ASIC1 in the hippocampus of rats in comparison with control animals. This was associated with the increase in IL-1β, IL-6 and TNF-α together with Caspase-3 and Caspase-9. The administration of amiloride into the lateral ventricle attenuated the upregulation of Caspase-3/Caspase-9 and this further alleviated neurological severity score and brain edema. Inhibition of central IL-6 and TNF-α also decreased ASIC1 in the hippocampus of CA rats. Conclusion: Transient global ischemia induced by CA amplifies ASIC1a in the hippocampus likely via PIC signal. Amiloride administered into the Central Nervous System plays a neuroprotective role in the process of global ischemia. Thus, targeting ASICs (i.e., ASIC1a) is suggested for the treatment and improvement of CA-evoked global cerebral ischemia.

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Multifocal glioblastoma multiform with “encephalitis-like presentation” : a case report

Egyptian Journal of Radiology and Nuclear Medicine ◽

10.1186/s43055-021-00407-2 ◽

2021 ◽

Vol 52 (1) ◽

Author(s):

Issam Sa’adeh ◽

Mohamed Jamal Saadh

Keyword(s):

Vasogenic Edema ◽

Neurological Deficits ◽

Herpes Simplex Virus 1 ◽

Glioblastoma Multiform ◽

Atypical Clinical Presentation ◽

Mri Scans ◽

The Central Nervous System ◽

Magnetic Resonance Imaging Mri ◽

Simplex Virus ◽

Multifocal Glioblastoma

Abstract Background Glioblastoma multiform is the most common and aggressive type of primary malignant tumor that affects the central nervous system in adults. It clinically presents with seizures, headache, and/or progressive focal neurological deficits. Radiologically, glioblastoma multiform appears as a single distinguishable, large heterogeneous lesion affecting the cerebrum with characteristic central necrosis, marginal enhancement, and surrounding vasogenic edema. This article describes a patient that exhibited an atypical clinical presentation of multifocal glioblastoma multiform with misleading early radiological features that simulated herpetic encephalitis. Results A 66-year-old female that presented with left-sided hemiparesis and left partial motor seizures underwent multi-slice computed tomography (MSCT) and magnetic resonance imaging (MRI) scans. A cerebrospinal fluid (CSF) polymerase chain reaction (PCR) test was also performed to screen for herpes simplex virus 1 (HSV-1). Conclusions The early stages of glioblastoma may manifest as symptoms typical to encephalitis, which can delay diagnosis and treatment. Therefore, early diagnosis and identification of atypical glioblastoma multiform presentations, as reported in this article, are essential.

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Clinical features, imaging findings and outcomes of headache associated with sexual activity

Cephalalgia ◽

10.1177/0333102410364675 ◽

2010 ◽

Vol 30 (11) ◽

pp. 1329-1335 ◽

Cited By ~ 41

Author(s):

Yen-Chi Yeh ◽

Jong-Ling Fuh ◽

Shih-Pin Chen ◽

Shuu-Jiun Wang

Keyword(s):

Sexual Activity ◽

Clinical Features ◽

Age At Onset ◽

Neurological Deficits ◽

Artery Dissection ◽

Imaging Findings ◽

Cerebral Vasoconstriction ◽

The Central Nervous System ◽

Headache Clinic ◽

Neurovascular Imaging

Objectives: To study the clinical profiles, imaging findings and outcomes and field test the diagnostic criteria proposed by the International Classification of Headache Disorders, 2nd edition (ICHD-II) in patients with headache associated with sexual activity (HSA). Methods: We recruited 30 patients (16 men, 14 women, mean age at onset 40.2 ± 10.0 years) with headache associated with sexual activity at a headache clinic from 2004 to 2009. None of the patients had neurological deficits at onset. Results: Twenty patients (67%) had secondary causes, including one subarachnoid hemorrhage, one basilar artery dissection, and 18 cases reversible cerebral vasoconstriction syndrome (RCVS). Ten patients (33%) had primary HSA. The demographics, headache profiles, drug response and clinical course were similar between primary and secondary HSA. Compared to prior studies done in Western societies, our patients had similar clinical features but with a higher ratio of females (50%) and a higher frequency of chronic course (39%). Discussion: Sixty-seven percent of patients with RCVS could not fulfill the criteria of reversible angiopathy of the central nervous system (Code 6.7.3) proposed by the ICHD-II. The most common reason was headache resolution in more than two months. In addition, 40% of patients with primary HSA could not fulfill the ICHD-II criteria for primary HSA (Code 4.4). Conclusions: Our study found that intracranial vascular disorders were very common in patients with HSA. Thorough neurovascular imaging is required for all patients with HSA.

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Extracellular Signal-Regulated Kinase Binds to TFII-I and Regulates Its Activation of the c-fosPromoter

Molecular and Cellular Biology ◽

10.1128/mcb.20.4.1140-1148.2000 ◽

2000 ◽

Vol 20 (4) ◽

pp. 1140-1148 ◽

Cited By ~ 37

Author(s):

Dae-Won Kim ◽

Brent H. Cochran

Keyword(s):

Map Kinase ◽

Transcriptional Activation ◽

Dominant Negative ◽

Binding Motif ◽

Dependent Manner ◽

Consensus Map ◽

Interaction Domain ◽

Extracellular Signal

ABSTRACT We have previously shown that TFII-I enhances transcriptional activation of the c-fos promoter through interactions with upstream elements in a signal-dependent manner. Here we demonstrate that activated Ras and RhoA synergize with TFII-I for c-fospromoter activation, whereas dominant-negative Ras and RhoA inhibit these effects of TFII-I. The Mek1 inhibitor, PD98059 abrogates the enhancement of the c-fos promoter by TFII-I, indicating that TFII-I function is dependent on an active mitogen-activated protein (MAP) kinase pathway. Analysis of the TFII-I protein sequence revealed that TFII-I contains a consensus MAP kinase interaction domain (D box). Consistent with this, we have found that TFII-I forms an in vivo complex with extracellular signal-related kinase (ERK). Point mutations within the consensus MAP kinase binding motif of TFII-I inhibit its ability to bind ERK and its ability to enhance the c-fos promoter. Therefore, the D box of TFII-I is required for its activity on the c-fos promoter. Moreover, the interaction between TFII-I and ERK can be regulated. Serum stimulation enhances complex formation between TFII-I and ERK, and dominant-negative Ras abrogates this interaction. In addition, TFII-I can be phosphorylated in vitro by ERK and mutation of consensus MAP kinase substrate sites at serines 627 and 633 impairs the phosphorylation of TFII-I by ERK and its activity on the c-fos promoter. These results suggest that ERK regulates the activity of TFII-I by direct phosphorylation.

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Cerebellar peduncle abscess secondary to disseminated strangles in a six-week-old miniature foal

Veterinary Science Development ◽

10.4081/vsd.2011.3516 ◽

2011 ◽

Vol 1 (1) ◽

pp. 12

Author(s):

Brianne Henderson

Keyword(s):

Animal Health ◽

Clinical Signs ◽

Acute Onset ◽

Abscess Formation ◽

Neurological Deficits ◽

Post Mortem ◽

Streptococcus Equi ◽

The Central Nervous System ◽

Cerebellar Peduncle ◽

The Right

During a strangles outbreak within a herd of minature horses, a six week old foal developed acute onset clinical signs of sepsis and neurological deficits. The foal was euthanized and submitted for post-mortem at the Animal Health Laboratories, Guelph Ontario. Gross post-mortem examination noted severe bronchopneumonia, hypopyon of the right eye and a singular cerebellar peduncle abscess. Culture of the lungs and cerebellum produced a pure growth of Streptococcus equi ssp. equi. Streptococcus equi ssp. equi, the causative agent of equine strangles, produces an acute pyrexia, purulent lymphadenopathy of submandibular and retropharyngeal lymph nodes. Commonly, lymph node abscesses rupture and resolve without complication. Rarely, complications may include: dissemination of the bacteria with diffuse abscess formation, immune mediated disease (purpura haemorrhagica), rarely abscess formation within the central nervous system (CNS) can occur. These can be managed medically with appropriate antibiotics and drugs to reduce intra-cranial pressure, however surgical drainage and debulking of the abscess has been attempted successfully in a few cases.

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Critical role of the extracellular signal–regulated kinase–MAPK pathway in osteoblast differentiation and skeletal development

The Journal of Cell Biology ◽

10.1083/jcb.200610046 ◽

2007 ◽

Vol 176 (5) ◽

pp. 709-718 ◽

Cited By ~ 337

Author(s):

Chunxi Ge ◽

Guozhi Xiao ◽

Di Jiang ◽

Renny T. Franceschi

Keyword(s):

Transcriptional Activity ◽

Mapk Pathway ◽

Skeletal Development ◽

Critical Role ◽

Dominant Negative ◽

Mitogen Activated Protein Kinase ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal

The extracellular signal–regulated kinase (ERK)–mitogen-activated protein kinase (MAPK) pathway provides a major link between the cell surface and nucleus to control proliferation and differentiation. However, its in vivo role in skeletal development is unknown. A transgenic approach was used to establish a role for this pathway in bone. MAPK stimulation achieved by selective expression of constitutively active MAPK/ERK1 (MEK-SP) in osteoblasts accelerated in vitro differentiation of calvarial cells, as well as in vivo bone development, whereas dominant-negative MEK1 was inhibitory. The involvement of the RUNX2 transcription factor in this response was established in two ways: (a) RUNX2 phosphorylation and transcriptional activity were elevated in calvarial osteoblasts from TgMek-sp mice and reduced in cells from TgMek-dn mice, and (b) crossing TgMek-sp mice with Runx2+/− animals partially rescued the hypomorphic clavicles and undemineralized calvaria associated with Runx2 haploinsufficiency, whereas TgMek-dn; Runx2+/− mice had a more severe skeletal phenotype. This work establishes an important in vivo function for the ERK–MAPK pathway in bone that involves stimulation of RUNX2 phosphorylation and transcriptional activity.

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The Hinge-Helix 1 Region of Peroxisome Proliferator-Activated Receptor γ1 (PPARγ1) Mediates Interaction with Extracellular Signal-Regulated Kinase 5 and PPARγ1 Transcriptional Activation: Involvement in Flow-Induced PPARγ Activation in Endothelial Cells

Molecular and Cellular Biology ◽

10.1128/mcb.24.19.8691-8704.2004 ◽

2004 ◽

Vol 24 (19) ◽

pp. 8691-8704 ◽

Cited By ~ 91

Author(s):

Masashi Akaike ◽

Wenyi Che ◽

Nicole-Lerner Marmarosh ◽

Shinsuke Ohta ◽

Masaki Osawa ◽

...

Keyword(s):

Endothelial Cells ◽

Adhesion Molecule ◽

Critical Role ◽

Physiological Role ◽

Cellular Adhesion ◽

Dominant Negative ◽

Peroxisome Proliferator ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal ◽

Cellular Adhesion Molecule

ABSTRACT Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors that form a subfamily of the nuclear receptor gene family. Since both flow and PPARγ have atheroprotective effects and extracellular signal-regulated kinase 5 (ERK5) kinase activity is significantly increased by flow, we investigated whether ERK5 kinase regulates PPARγ activity. We found that activation of ERK5 induced PPARγ1 activation in endothelial cells (ECs). However, we could not detect PPARγ phosphorylation by incubation with activated ERK5 in vitro, in contrast to ERK1/2 and JNK, suggesting a role for ERK5 as a scaffold. Endogenous PPARγ1 was coimmunoprecipitated with endogenous ERK5 in ECs. By mammalian two-hybrid analysis, we found that PPARγ1 associated with ERK5a at the hinge-helix 1 region of PPARγ1. Expressing a hinge-helix 1 region PPARγ1 fragment disrupted the ERK5a-PPARγ1 interaction, suggesting a critical role for hinge-helix 1 region of PPARγ in the ERK5-PPARγ interaction. Flow increased ERK5 and PPARγ1 activation, and the hinge-helix 1 region of the PPARγ1 fragment and dominant negative MEK5β significantly reduced flow-induced PPARγ activation. The dominant negative MEK5β also prevented flow-mediated inhibition of tumor necrosis factor alpha-mediated NF-κB activation and adhesion molecule expression, including vascular cellular adhesion molecule 1 and E-selectin, indicating a physiological role for ERK5 and PPARγ activation in flow-mediated antiinflammatory effects. We also found that ERK5 kinase activation was required, likely by inducing a conformational change in the NH2-terminal region of ERK5 that prevented association of ERK5 and PPARγ1. Furthermore, association of ERK5a and PPARγ1 disrupted the interaction of SMRT and PPARγ1, thereby inducing PPARγ activation. These data suggest that ERK5 mediates flow- and ligand-induced PPARγ activation via the interaction of ERK5 with the hinge-helix 1 region of PPARγ.

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