Low levels of ALS-linked Cu/Zn superoxide dismutase increase the production of reactive oxygen species and cause mitochondrial damage and death in motor neuron-like cells

Rizzardini, Milena; Mangolini, Alessandra; Lupi, Monica; Ubezio, Paolo; Bendotti, Caterina; Cantoni, L

doi:10.1016/j.jns.2005.02.004

Cited by 66 publications

(66 citation statements)

References 47 publications

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“…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).…”

Section: Genetic-linked Alterations In Lactate Homeostasis Underlyingmentioning

confidence: 99%

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: Genetic-linked Alterations In Lactate Homeostasis Underlyingmentioning

confidence: 99%

Lactate dyscrasia: a novel explanation for amyotrophic lateral sclerosis

Meethal

Atwood

2012

Neurobiology of Aging

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“…Based on studies in both transgenic mice (Bowling et al, 1993;Higgins et al, 2002Higgins et al, , 2003Mattiazzi et al, 2002Mattiazzi et al, , 2004Liu et al, 2004;Kirkinezos et al, 2005;Vijayvergiya et al, 2005) and cultured cells (Rizzardini et al, 2005;Cozzolino et al, 2006), mitochondria have been suggested to be the primary targets. There are, however, complicating circumstances in the murine ALS models.…”

Section: Introductionmentioning

confidence: 99%

Overloading of Stable and Exclusion of Unstable Human Superoxide Dismutase-1 Variants in Mitochondria of Murine Amyotrophic Lateral Sclerosis Models

Bergemalm

Jonsson²,

Graffmo³

et al. 2006

J. Neurosci.

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Mutants of human superoxide dismutase-1 (hSOD1) cause amyotrophic lateral sclerosis (ALS), and mitochondria are thought to be primary targets of the cytotoxic action. The high expression rates of hSOD1s in transgenic ALS models give high levels of the stable mutants G93A and D90A as well as the wild-type human enzyme, significant proportions of which lack Cu and the intrasubunit disulfide bond. The endogenous murine SOD1 (mSOD1) also lacks Cu and is disulfide reduced but is active and oxidized in mice expressing the low-level unstable mutants G85R and G127insTGGG. The possibility that the molecular alterations may cause artificial loading of the stable hSOD1s into mitochondria was explored. Approximately 10% of these hSOD1s were localized to mitochondria, reaching levels 100-fold higher than those of mSOD1 in control mice. There was no difference between brain and spinal cord and between stable mutants and the wild-type hSOD1. mSOD1 was increased fourfold in mitochondria from high-level hSOD1 mice but was normal in those with low levels, suggesting that the Cu deficiency and disulfide reduction cause mitochondrial overloading. The levels of G85R and G127insTGGG mutant hSOD1s in mitochondria were 100-and 1000-fold lower than those of stable mutants. Spinal cords from symptomatic mice contained hSOD1 aggregates covering the entire density gradient, which could contaminate isolated organelle fractions. Thus, high hSOD1 expression rates can cause artificial loading of mitochondria. Unstable low-level hSOD1s are excluded from mitochondria, indicating other primary locations of injury. Such models may be preferable for studies of ALS pathogenesis.

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“…The NSC-34 cell line (a kind gift from N. R. Cashman) was used to obtain lines stably expressing human wild-type SOD1 (WT-NSC) or G93ASOD1 (G93A-NSC) as described previously (Rizzardini et al 2005). The G93A-NSC cell line expresses a low level of G93ASOD1 (lower than murine SOD1) and therefore it appears a good model of motor neurons in the disease in terms of expression level since only one allele is mutant in FALS patients with SOD1 mutations.…”

Section: Motor Neuronal Als Modelmentioning

confidence: 99%

“…In this study, we utilized a well-characterized FALS motor neuronal model over-expressing G93A mutant human SOD1, (Rizzardini et al 2005), the pathogenic mutant SOD1 more extensively studied. We found that when this mutant protein was expressed, exposure to low O 2 caused greater cell loss, disabled autophagy, and altered reprogramming of metabolism suggesting that a defective adaptation to this stress may contribute to the neurodegenerative process.…”

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confidence: 99%

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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Low levels of ALS-linked Cu/Zn superoxide dismutase increase the production of reactive oxygen species and cause mitochondrial damage and death in motor neuron-like cells

Cited by 66 publications

References 47 publications

Lactate dyscrasia: a novel explanation for amyotrophic lateral sclerosis

Lactate dyscrasia: a novel explanation for amyotrophic lateral sclerosis

Overloading of Stable and Exclusion of Unstable Human Superoxide Dismutase-1 Variants in Mitochondria of Murine Amyotrophic Lateral Sclerosis Models

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

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