Analysis of the Cytosolic Proteome in a Cell Culture Model of Familial Amyotrophic Lateral Sclerosis Reveals Alterations to the Proteasome, Antioxidant Defenses, and Nitric Oxide Synthetic Pathways

Allen, Simon; Heath, Paul R.; Kirby, Janine; Wharton, Stephen B.; Cookson, Mark; Menzies, Fiona M.; Banks, Rosamonde E.; Shaw, Pamela J.

doi:10.1074/jbc.m209915200

Cited by 111 publications

(71 citation statements)

References 72 publications

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“…Our published data led us to believe that these would constitute a subset of proteins activated by Fas and involved in SOD1-related cell death (Raoul et al, 2002). In contrast, a comparable proteomic study analyzed the effects of stable overexpression of mSOD1 in the motoneuron-like cell line NSC34 (Allen et al, 2003). This study identified several changes that could be confirmed in postmortem material from ALS patients.…”

Section: Discussionmentioning

confidence: 91%

Collapsin Response Mediator Protein 4a (CRMP4a) Is Upregulated in Motoneurons of Mutant SOD1 Mice and Can Trigger Motoneuron Axonal Degeneration and Cell Death

Duplan¹,

Bernard²,

Casseron³

et al. 2010

J. Neurosci.

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Embryonic motoneurons from mutant SOD1 (mSOD1) mouse models of amyotrophic lateral sclerosis (ALS), but not wild-type motoneurons, can be triggered to die by exposure to nitric oxide (NO), leading to activation of a motoneuron-specific signaling pathway downstream of the death receptor Fas/CD95. To identify effectors of mSOD1-dependent cell death, we performed a proteomic analysis. Treatment of cultured mSOD1 motoneurons with NO led to a 2.5-fold increase in levels of collapsin response mediator protein 4a (CRMP4a). In vivo, the percentage of mSOD1 lumbar motoneurons expressing CRMP4 in mSOD1 mice increased progressively from presymptomatic to early-onset stages, reaching a maximum of 25%. Forced adeno-associated virus (AAV)-mediated expression of CRMP4a in wild-type motoneurons in vitro triggered a process of axonal degeneration and cell death affecting 60% of motoneurons, whereas silencing of CRMP4a in mSOD1 motoneurons protected them from NO-induced death. In vivo, AAV-mediated overexpression of CRMP4a but not CRMP2 led to the death of 30% of the lumbar motoneurons and an 18% increase in denervation of neuromuscular junctions in the gastrocnemius muscle. Our data identify CRMP4a as a potential early effector in the neurodegenerative process in ALS.

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Section: Discussionmentioning

confidence: 91%

Collapsin Response Mediator Protein 4a (CRMP4a) Is Upregulated in Motoneurons of Mutant SOD1 Mice and Can Trigger Motoneuron Axonal Degeneration and Cell Death

Duplan¹,

Bernard²,

Casseron³

et al. 2010

J. Neurosci.

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“…4) (55). Diseases in which protein nitration and mitochondrial dysfunctions are observed include Parkinsons disease, diabetes, and amyotrophic lateral sclerosis (3,26,57). Mitochondria play a critical role in energy production and apoptosis, and these functions are affected by NO and related oxides (59).…”

Section: Resultsmentioning

confidence: 99%

Dynamics of protein nitration in cells and mitochondria

Aulak

Koeck

Crabb

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

175

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Aulak, Kulwant S., Thomas Koeck, John W. Crabb, and Dennis J. Stuehr. Dynamics of protein nitration in cells and mitochondria. Am J Physiol Heart Circ Physiol 286: H30-H38, 2004; 10.1152/ ajpheart.00743.2003.-Nitric oxide is a precursor of reactive nitrating species such as peroxynitrite and nitrogen dioxide that modify proteins to generate 3-nitrotyrosine. Many diseases are associated with increased levels of protein-bound nitrotyrosine, and this is used as a marker for oxidative damage. However, the regulation of protein nitration and its role in cell function are unclear. We demonstrate that biological protein nitration can be a specific and dynamic process. Proteins were nitrated in distinct temporal patterns in cells undergoing inflammatory activation, and protein denitration and renitration occurred rapidly in respiring mitochondria. The targets of protein nitration varied over time, which may reflect their sensitivity to nitration, expression pattern, or turnover. The dynamic nature of the nitration process was revealed by denitration and renitration of proteins occurring within minutes in mitochondria that were subject to hypoxiaanoxia and reoxygenation. Our results have implications that are particularly important for ischemia-reperfusion injury.

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“…Proteome analysis reveals up-regulation of PRX1 and PRX6 in experimental models of familial amyotrophic lateral sclerosis (66,67). Using both in vivo and in vitro models of excitotoxic injury, two independent studies indicate that overexpression of PRX3 or PRX5 provides a certain degree of neuroprotection in these models (68,69), thereby providing evidence for the involvement of certain isoforms of PRX in the progression of neurodegenerative disorders.…”

Section: Discussionmentioning

confidence: 99%

Oxidative Modification of Peroxiredoxin Is Associated with Drug-induced Apoptotic Signaling in Experimental Models of Parkinson Disease

Lee

Park

Shin

et al. 2008

Journal of Biological Chemistry

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The aim of this study was to investigate changes in protein profiles during the early phase of dopaminergic neuronal death using two-dimensional gel electrophoresis in conjunction with mass spectrometry. Several protein spots were identified whose expression was significantly altered following treatment of MN9D dopaminergic neuronal cells with 6-hydroxydopamine (6-OHDA). In particular, we detected oxidative modification of thioredoxin-dependent peroxidases (peroxiredoxins; PRX) in treated MN9D cells. Oxidative modification of PRX induced by 6-OHDA was blocked in the presence of N-acetylcysteine, suggesting that reactive oxygen species (ROS) generated by 6-OHDA induce oxidation of PRX. These findings were confirmed in primary cultures of mesencephalic neurons and in rat brain injected stereotaxically. Overexpression of PRX1 in MN9D cells (MN9D/PRX1) exerted neuroprotective effects against death induced by 6-OHDA through scavenging of ROS. Consequently, generation of both superoxide anion and hydrogen peroxide following 6-OHDA treatment was decreased in MN9D/PRX1. Furthermore, overexpression of PRX1 protected cells against 6-OHDA-induced activation of p38 MAPK and subsequent activation of caspase-3. In contrast, 6-OHDA-induced apoptotic death signals were enhanced by RNA interference-targeted reduction of PRX1 in MN9D cells. Taken together, our data suggest that the redox state of PRX may be intimately involved in 6-OHDA-induced dopaminergic neuronal cell death and also provide a molecular mechanism by which PRX1 exerts a protective role in experimental models of Parkinson disease. Parkinson disease (PD)3 is a common neurodegenerative disorder characterized by progressive degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (1). Clinical manifestations, such as resting tremor, slowness of movement, stiffness, and postural instability in patients with PD are consequences of the loss of DA neurons and the resulting depletion of dopamine in the striatum. Most PD cases are sporadic, and its etiology is incompletely understood; however, an increasing body of evidence suggests that oxidative stress, mitochondrial dysfunction, and impairment of the ubiquitinproteasome system may be involved in the pathogenesis of PD (2-5). Recent studies indicate that mutations in several genes appear to cause a familial form of PD (6), and mutations in these genes seem to share common pathways underlying the pathogenesis of a sporadic form of PD.DA neurons are vulnerable to neurodegeneration because of their high levels of reactive oxygen species (ROS) (7); enzymatic metabolism of dopamine produces hydrogen peroxide and superoxide radicals, and intracellular autoxidation of dopamine induces the formation of dopamine-quinone, leading to the generation of hydroxyl radical when combined with iron (7, 8). Furthermore, there is a significant alteration in levels or activities of antioxidant enzymes in the substantia nigra (9 -13). Among many potential consequences of oxidative stress, surges in ROS render DA neuron...

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Analysis of the Cytosolic Proteome in a Cell Culture Model of Familial Amyotrophic Lateral Sclerosis Reveals Alterations to the Proteasome, Antioxidant Defenses, and Nitric Oxide Synthetic Pathways

Cited by 111 publications

References 72 publications

Collapsin Response Mediator Protein 4a (CRMP4a) Is Upregulated in Motoneurons of Mutant SOD1 Mice and Can Trigger Motoneuron Axonal Degeneration and Cell Death

Collapsin Response Mediator Protein 4a (CRMP4a) Is Upregulated in Motoneurons of Mutant SOD1 Mice and Can Trigger Motoneuron Axonal Degeneration and Cell Death

Dynamics of protein nitration in cells and mitochondria

Oxidative Modification of Peroxiredoxin Is Associated with Drug-induced Apoptotic Signaling in Experimental Models of Parkinson Disease

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