Gain of interaction of ALS-linked G93A superoxide dismutase with cytosolic malate dehydrogenase

Mali, Yael; Zisapels, Nava

doi:10.1016/j.nbd.2008.06.010

Cited by 18 publications

(23 citation statements)

References 33 publications

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“…Evidence supporting the MNLS model includes: (1) the concentration of serum lactic acid is higher in persons with ALS (2.77 Ϯ 0.79 mmol/L) and chronic denervated non-ALS patients (2.79 Ϯ 1.29 mmol/L) compared with controls (1.48 Ϯ 0.49 mmol/L) (Siciliano et al, 2001); (2) lactic acid can induce death in neurons (Nedergaard et al, 1991); (3) increased lactate concentrations have been reported in other neurodegenerative conditions such as Huntington disease (Bowling and Beal, 1995) as well as in models of severe and mild brain injury (Ramonet et al, 2004); (4) neuroprotective drugs like nizofenone that block lactate accumulation are used to treat other neurodegenerative diseases ; (5) lactate metabolism in ALS is associated with glutamate excitotoxicity related to neuronal degeneration (Shobha et al, 2007); (6) mitochondrial oxidative phosphorylation is dysfunctional in SOD1 G93A transgenic mice (Jung et al, 2002;Mattiazzi et al, 2002;Vijayvergiya et al, 2005); (7) the malate-aspartate shuttle is inhibited in hSOD1 G93A expressing cells (Mali and Zisapels, 2008) and this may explain the elevated levels of lactate and the damage to neurons (Mali and Zisapels, 2008); (8) hSOD1 G93A -expressing cells showed increased concentrations of cytoplasmic malate dehydrogenase messenger ribonucleic acid (mRNA), malate, and lactate compared with noninduced or wild-type-hSOD1-expressing cells (Mali and Zisapels, 2008); (9) the mitochondrial NADH/NADϩ ratio is elevated in hSOD1 G93A -expressing cells indicating an increased conversion of oxaloacetate to malate in the mitochondria by NADH-dependent mitochondrial malate dehydrogenase MDH (Mali and Zisapels, 2008); (10) impairments in the malate-aspartate shuttle which controls the brain mitochondrial NADH/NAD ϩ balance is known to drive anaerobic metabolism (particularly damaging to neurons) as well as vulnerability to impairments of glycolytic pathways (Mali and Zisapels, 2008); (11) impaired oxidative metabolism and accumulation of lactate was reported in exercising ALS patients (Siciliano et al, 2001);and (12) functional motor unit failure precedes neuromuscular degeneration in motoneuron disease (Balice- Gordon et al, 2000;Fischer et al, 2004).…”

Section: Evidence For the Molecular Modelmentioning

confidence: 99%

“…Although loss of catalytic hSOD1 activity has been implicated and mitochondrial ROS is associated with the mechanism underlying denervation-induced atrophy (Muller et al, 2007) in familial ALS, the nature of the toxicity is poorly understood (Carri et al, 1997;Kruman et al, 1999;Rizzardini et al, 2005). Evidence for mutations in SOD1 as driving the pathogenesis of ALS has been reported in cell systems and mice overexpressing the hSOD1 G93A protein as described above (Jung et al, 2002;Mali and Zisapels, 2008;Mattiazzi et al, 2002;Vijayvergiya et al, 2005). These systems suggest that FALS-related mutations alter lactate homeostasis leading to the pathophysiology of FALS.…”

Section: Genetic-linked Alterations In Lactate Homeostasis Underlyingmentioning

confidence: 99%

“…Suppression of hSOD1 G93A expression in both motor neurons and muscle was sufficient to maintain grip strength. The requirement for reduction of the expression of hSOD1 G93A in both muscle and motoneurons to effect an increase in muscle strength suggests that decreases in the aberrant activity of this protein in all cell types is required to reverse the dysfunctional mitochondrial oxidative phosphorylation (Jung et al, 2002;Mattiazzi et al, 2002;Vijayvergiya et al, 2005) and malateaspartate shuttle inhibition in hSOD1 G93A expressing cells (Mali and Zisapels, 2008), and that lactate production in the motoneuron may preferentially effect disease progression.…”

Section: Genetic-linked Alterations In Lactate Homeostasis Underlyingmentioning

confidence: 99%

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Lactate dyscrasia: a novel explanation for amyotrophic lateral sclerosis

Meethal

Atwood

2012

Neurobiology of Aging

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Amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease) is a progressive debilitating neurodegenerative disease with no cure. We propose a novel molecular model for the pathogenesis of ALS that involves an adenosine triphosphate (ATP)-dependent muscle neuronal lactate shuttle (MNLS) at the neuromuscular junction (NMJ) to regulate the flow of lactate from muscle to neurons and vice versa. Failure of the MNLS due to respiratory chain dysfunction is proposed to result in lactate toxicity and degeneration of nerve endings at the NMJ leading to nerve terminus dysjunction from the muscle cell. At a critical threshold where denervation outpaces reinnervation, a vicious cycle is established where the remaining innervated muscle fibers are required to work harder to compensate for normal function, and in so doing produce toxic lactate concentrations which induces further denervation and neuronal death. This mechanism explains the exponential progression of ALS leading to paralysis. The molecular events leading to the dysregulation of the MNLS and the dismantling of NMJ are explained in the context of known ALS familial mutations and age-related endocrine dyscrasia. Combination drug therapies that inhibit lactate accumulation at the NMJ, enhance respiratory chain function, and/or promote reinnervation are predicted to be effective therapeutic strategies for ALS. Published by Elsevier Inc.

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Section: Evidence For the Molecular Modelmentioning

confidence: 99%

Section: Genetic-linked Alterations In Lactate Homeostasis Underlyingmentioning

confidence: 99%

Section: Genetic-linked Alterations In Lactate Homeostasis Underlyingmentioning

confidence: 99%

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Lactate dyscrasia: a novel explanation for amyotrophic lateral sclerosis

Meethal

Atwood

2012

Neurobiology of Aging

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“…Earlier studies in normoxic conditions with NSC-34 cell lines stably expressing high/low levels of human mutant SOD1 transgenes and cultured with/without the addition of oxidants highlighted alterations to metabolic markers, including some of those examined in this study (Mali and Zisapels 2008;Mali and Zisapel 2010;D'Alessandro et al 2011;Richardson et al 2013). Reduced O 2 concentration is also a stimulus causing enhanced ROS formation; these results as a whole suggest that oxidative stress causes significant metabolic derangements and this occurs when cells express either a high level of mutant SOD1 or a low level but are exposed to oxidants.…”

Section: Discussionmentioning

confidence: 54%

Hypoxia causes autophagic stress and derangement of metabolic adaptation in a cell model of amyotrophic lateral sclerosis

Cimini

Rizzardini

Biella

et al. 2014

Journal of Neurochemistry

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Amyotrophic lateral sclerosis is a fatal neurodegenerative disease that affects motor neurons. The recruitment of autophagy (macroautophagy) and mitochondrial dysfunction are documented in amyotrophic lateral sclerosis patients and experimental models expressing mutant forms of Cu, Zn superoxide dismutase (SOD1) protein, but their impact in the disease remains unclear. Hypoxia is a stress closely related to the disease in patients and mutant SOD1 mice; in individual cells, hypoxia activates autophagy and regulates mitochondrial metabolism as fundamental adaptive mechanisms. Our aim was to examine whether mutant SOD1 changed this response. Hypoxia (1% O 2 for 22 h) caused greater loss of viability and more marked activation of caspase 3/7 in the motor neuronal NSC-34 cell line stably transfected with the G93A mutant human SOD1 (G93A-NSC) than in the one with the wild-type SOD1 (WT-NSC) or in untransfected NSC-34. In the G93A-NSC cells, there was a more marked accumulation of the LC3-II autophagy protein, attributable to autophagic stress; 3-methyladenine, which acts on initiation of autophagy, fully rescued G93A-NSC viability and reduced the activation of caspase 3/7 indicating this was a secondary event; the metabolic handling of hypoxia was inappropriate possibly contributing to the autophagic stress. Our findings evidentiate that the G93A mutation of SOD1 profoundly altered the adaptive metabolic response to hypoxia and this could increase the cell susceptibility to this stress. Keywords: 3-methyladenine, amyotrophic lateral sclerosis, autophagy, Cu, Zn superoxide dismutase, hypoxia, mitochondria. Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron neurodegenerative disease; it is rapidly fatal and has no therapy (Robberecht and Philips 2013). ALS is traditionally classified into familial and sporadic ALS (FALS and SALS), which are clinically very similar. FALS is caused by mutations in a heterogeneous group of genes; approximately 2% of ALS patients have mutations in the Cu, Zn superoxide dismutase (SOD1) gene; more than 150 different mutations, distributed in all the exons coding for the protein, have been reported to be pathogenic; their pathophysiological role is not clear, however, the mechanism(s) of toxicity is independent of the dismutase activity (Duffy et al. 2011;Robberecht and Philips 2013). In vitro and in vivo models over-expressing mutant forms of SOD1 are widely used for deciphering the neurodegenerative mechanisms involved in ALS.Hypoxia is a risk factor for neurodegenerative diseases including Alzheimer's disease, the main cause of dementia, (Zhang and Le 2010) and it is a stress which is closely related Received November 18, 2013; revised manuscript received December 13, 2013; accepted December 17, 2013. Address correspondence and reprint requests to Lavinia Cantoni, Laboratory of Molecular Pathology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via G. La Masa 19, 20156 Milan, Italy. E-mail: lavinia.cantoni@marionegri.it 1 These authors cont...

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“…cytMDH is a part of the malate-aspartate shuttle, controlling the brain mitochondrial NADH/NAD + balance. Impairments in this shuttle may enforce anaerobic metabolism [156]. …”

Section: Csa’s Effect On Transcriptional Regulationmentioning

confidence: 99%

Molecular Dissection of Cyclosporin A’s Neuroprotective Effect Reveals Potential Therapeutics for Ischemic Brain Injury

Kawakami

2013

Brain Sciences

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After the onset of brain ischemia, a series of events leads ultimately to the death of neurons. Many molecules can be pharmacologically targeted to protect neurons during these events, which include glutamate release, glutamate receptor activation, excitotoxicity, Ca2+ influx into cells, mitochondrial dysfunction, activation of intracellular enzymes, free radical production, nitric oxide production, and inflammation. There have been a number of attempts to develop neuroprotectants for brain ischemia, but many of these attempts have failed. It was reported that cyclosporin A (CsA) dramatically ameliorates neuronal cell damage during ischemia. Some researchers consider ischemic cell death as a unique process that is distinct from both apoptosis and necrosis, and suggested that mitochondrial dysfunction and Δψ collapse are key steps for ischemic cell death. It was also suggested that CsA has a unique neuroprotective effect that is related to mitochondrial dysfunction. Here, I will exhibit examples of neuroprotectants that are now being developed or in clinical trials, and will discuss previous researches about the mechanism underlying the unique CsA action. I will then introduce the results of our cDNA subtraction experiment with or without CsA administration in the rat brain, along with our hypothesis about the mechanism underlying CsA’s effect on transcriptional regulation.

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Gain of interaction of ALS-linked G93A superoxide dismutase with cytosolic malate dehydrogenase

Cited by 18 publications

References 33 publications

Lactate dyscrasia: a novel explanation for amyotrophic lateral sclerosis

Lactate dyscrasia: a novel explanation for amyotrophic lateral sclerosis

Hypoxia causes autophagic stress and derangement of metabolic adaptation in a cell model of amyotrophic lateral sclerosis

Molecular Dissection of Cyclosporin A’s Neuroprotective Effect Reveals Potential Therapeutics for Ischemic Brain Injury

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