VEGF up-regulation by G93A superoxide dismutase and the role of malate–aspartate shuttle inhibition

Mali, Yael; Zisapel, Nava

doi:10.1016/j.nbd.2009.12.005

Cited by 12 publications

(4 citation statements)

References 39 publications

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“…Besides providing electrons for oxidative phosphorylation, the malate-aspartate-NADH shuttle also generates glutamate and aspartate, and we showed impaired alanine, aspartate and glutamate metabolism in the serum of ALS patients. Dysfunctions in the malate-aspartate shuttle increase the vulnerability of neurons to glycolysis impairment and were demonstrated in cellular ALS models [ 63 , 64 , 65 ]. Further studies should focus on understanding the molecular mechanisms involved with the possible toxic effect of high citramalate levels, and to validate the application of this new putative biomarker for ALS diagnosis.…”

Section: Discussionmentioning

confidence: 99%

Metabolic Profile and Pathological Alterations in the Muscle of Patients with Early-Stage Amyotrophic Lateral Sclerosis

et al. 2022

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Diverse biomarkers and pathological alterations have been found in muscle of patients with Amyotrophic lateral sclerosis (ALS), but the relation between such alterations and dysfunction in energetic metabolism remains to be investigated. We established the metabolome of muscle and serum of ALS patients and correlated these findings with the clinical status and pathological alterations observed in the muscle. We obtained data from 20 controls and 17 ALS patients (disease duration: 9.4 ± 6.8 months). Multivariate metabolomics analysis identified a distinct serum metabolome for ALS compared to controls (p-CV-ANOVA < 0.035) and revealed an excellent discriminant profile for muscle metabolome (p-CV-ANOVA < 0.0012). Citramalate was discriminant for both muscle and serum. High lauroylcarnitine levels in muscle were associated with low Forced Vital Capacity. Transcriptomics analysis of key antioxidant enzymes showed an upregulation of SOD3 (p = 0.0017) and GLRX2(1) (p = 0.0022) in ALS muscle. Analysis of mitochondrial enzymatic activity in muscle revealed higher complex II/CS (p = 0.04) and lower LDH (p = 0.03) activity in ALS than in controls. Our study showed, for the first time, a global dysfunction in the muscle of early-stage ALS patients. Furthermore, we identified novel metabolites to be employed as biomarkers for diagnosis and prognosis of ALS patients.

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Section: Discussionmentioning

confidence: 99%

Metabolic Profile and Pathological Alterations in the Muscle of Patients with Early-Stage Amyotrophic Lateral Sclerosis

et al. 2022

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“…Li et al, 2009; L. Lu et al, 2009; Mali & Zisapel, 2010)). Attempts to manipulate VEGF-A levels in follow-up work utilized mice that were a cross breed of SOD1 G93A VEGF-A δ/δ strains which resulted in mice with an earlier onset of motor neuron disease and earlier death (Lambrechts et al, 2003).…”

Section: Evidence For the Role Of Vascular Endothelial Growth Factmentioning

confidence: 99%

Gene and protein therapies utilizing VEGF for ALS

Keifer

O’Connor

Boulis

2014

Pharmacology & Therapeutics

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that is usually fatal within 2–5 years. Unfortunately, the only treatment currently available is riluzole, which has a limited efficacy. As a redress, there is an expanding literature focusing on other potential treatments. One such potential treatment option utilizes the vascular endothelial growth factor (VEGF) family, which includes factors that are primarily associated with angiogenesis but are now increasingly recognized to have neurotrophic effects. Reduced expression of a member of this family, VEGF-A, in mice results in neurodegeneration similar to that of ALS, while treatment of animal models of ALS with either VEGF-A gene therapy or VEGF-A protein has yielded positive therapeutic outcomes. These basic research findings raise the potential for a VEGF therapy to be translated to the clinic for the treatment of ALS. This review covers the VEGF family, its receptors and neurotrophic effects as well as VEGF therapy in animal models of ALS and advances towards clinical trials.

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“…This further supports the conclusion that for this protein, the increase at the plasma membrane is due to poor COPI function rather than SMN-dependent changes in global rates of endocytosis. To assess COPI function in an independent model of motor neuron disease; we examined NSC-34 cells expressing doxycycline inducible SOD1 protein, either wild type or the G93A mutant that is associated with familial ALS (Mali and Zisapel, 2010). These cells did not exhibit an increase in myc-KA2 at the cell surface after SOD1 induction (Figure 5e).…”

Section: Alpha-cop Dependent Intracellular Trafficking Is Affected Under Conditions Of Low Smnmentioning

confidence: 99%

Abnormal Golgi morphology and decreased COPI function in cells with low levels of SMN

et al. 2019

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We report here the finding of abnormal Golgi apparatus morphology in motor neuron like cells depleted of SMN as well as Golgi apparatus morphology in SMA patient fibroblasts. Rescue experiments demonstrate that this abnormality is dependent on SMN, but can also be rescued by expression of the COPI coatomer subunit alpha-COP. A motor neuron-like cell line containing an inducible alpha-COP shRNA was created to generate a parallel system to study knockdown of SMN or alpha-COP. Multiple assays of COPI-dependent intracellular trafficking in cells depleted of SMN demonstrate that alpha-COP function is suboptimal, including failed sequestration of plasma membrane proteins, altered binding of mRNA, and defective targeting and transport of Golgi-resident proteins.

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VEGF up-regulation by G93A superoxide dismutase and the role of malate–aspartate shuttle inhibition

Cited by 12 publications

References 39 publications

Metabolic Profile and Pathological Alterations in the Muscle of Patients with Early-Stage Amyotrophic Lateral Sclerosis

Metabolic Profile and Pathological Alterations in the Muscle of Patients with Early-Stage Amyotrophic Lateral Sclerosis

Gene and protein therapies utilizing VEGF for ALS

Abnormal Golgi morphology and decreased COPI function in cells with low levels of SMN

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