Activation of the p38MAPK cascade is associated with upregulation of TNF alpha receptors in the spinal motor neurons of mouse models of familial ALS

Veglianese, Pietro; Coco, Daniele Lo; Cutrona, M. Bao; Magnoni, R.; Pennacchini, Danilo; Pozzi, Bruna; Gowing, Genevíève; Julien, J.P.; Tortarolo, Massimo; Bendotti, Caterina

doi:10.1016/j.mcn.2005.09.009

Cited by 93 publications

(61 citation statements)

References 67 publications

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“…Staurosporin is known to induce apoptosis by activation of the caspase cascade as well as through generation of reactive oxygen species [30][31]. Treatment with H 2 O 2 results in oxidative damage as well as activation of p38 MAPK [32] that has also been implicated in ALS [33][34][35]. There are several lines of evidence that indicate that hsps can promote motoneuron survival.…”

Section: Discussionmentioning

confidence: 99%

Activation of the heat shock response in a primary cellular model of motoneuron neurodegeneration-evidence for neuroprotective and neurotoxic effects

Kalmár¹,

Greensmith²

2009

Cellular and Molecular Biology Letters

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Abbreviations used: ALS -Amyotrophic Lateral Sclerosis; HSF-1 -heat shock factor-1; hsp -heat shock protein; HSR -heat shock response Research article ACTIVATION OF THE HEAT SHOCK RESPONSE IN A PRIMARY CELLULAR MODEL OF MOTONEURON NEURODEGENERATION -EVIDENCE FOR NEUROPROTECTIVE AND NEUROTOXIC EFFECTSBERNADETT KALMAR* and LINDA GREENSMITH Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, United KingdomAbstract: Pharmacological up-regulation of heat shock proteins (hsps) rescues motoneurons from cell death in a mouse model of amyotrophic lateral sclerosis. However, the relationship between increased hsp expression and neuronal survival is not straightforward. Here we examined the effects of two pharmacological agents that induce the heat shock response via activation of HSF-1, on stressed primary motoneurons in culture. Although both arimoclomol and celastrol induced the expression of Hsp70, their effects on primary motoneurons in culture were significantly different. Whereas arimoclomol had survival-promoting effects, rescuing motoneurons from staurosporin and H 2 O 2 induced apoptosis, celastrol not only failed to protect stressed motoneurons from apoptosis under same experimental conditions, but was neurotoxic and induced neuronal death. Immunostaining of celastrol-treated cultures for hsp70 and activated caspase-3 revealed that celastrol treatment activates both the heat shock response and the apoptotic cell death cascade. These results indicate that not all agents that activate the heat shock response will necessarily be neuroprotective.

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Section: Discussionmentioning

confidence: 99%

Activation of the heat shock response in a primary cellular model of motoneuron neurodegeneration-evidence for neuroprotective and neurotoxic effects

Kalmár¹,

Greensmith²

2009

Cellular and Molecular Biology Letters

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“…Tissues were sectioned in the sagittal plane (10 m thick). Immunofluorescence on tissue sections was performed as described previously (Veglianese et al, 2006). They were blocked with 10% donkey serum and 0.4% Triton X-100 in 1ϫ PBS, incubated overnight at 4°C with the primary antibody, washed in 1ϫ PBS, and incubated with the appropriate Alexa488/ Alexa596-conjugated donkey secondary antibodies.…”

Section: Methodsmentioning

confidence: 99%

Haploinsufficiency ofAFG3L2, the Gene Responsible for Spinocerebellar Ataxia Type 28, Causes Mitochondria-Mediated Purkinje Cell Dark Degeneration

Maltecca¹,

Magnoni²,

Cerri³

et al. 2009

J. Neurosci.

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101

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Paraplegin and AFG3L2 are ubiquitous nuclear-encoded mitochondrial proteins that form hetero-oligomeric paraplegin-AFG3L2 and homo-oligomeric AFG3L2 complexes in the inner mitochondrial membrane, named m-AAA proteases. These complexes ensure protein quality control in the inner membrane, jointly with a chaperone-like activity on the respiratory chain complexes. Despite coassembling in the same complex, mutations of either paraplegin or AFG3L2 cause two different neurodegenerative disorders. Indeed, mutations of paraplegin are responsible for a recessive form of hereditary spastic paraplegia, whereas mutations of AFG3L2 have been recently associated to a dominant form of spinocerebellar ataxia (SCA28). In this work, we report that the mouse model haploinsufficient for Afg3l2 recapitulates important pathophysiological features of the human disease, thus representing the first SCA28 model. Furthermore, we propose a pathogenetic mechanism in which respiratory chain dysfunction and increased reactive oxygen species production caused by Afg3l2 haploinsufficiency lead to dark degeneration of Purkinje cells and cerebellar dysfunction.

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“…Upregulation of TNFα and TNF receptors is observed in parallel with the appearance of symptoms in SOD1 mice [23,24] and increased levels of TNFα are found in plasma of ALS patients [25]. However, genetic ablation of TNFα has no beneficial effect on survival, motor axon degeneration or gliosis in either of two different lines of mutant SOD1 mice [26•].…”

Section: Involvement Of Death Receptors In Disease Mechanism and Thermentioning

confidence: 99%

Signaling by death receptors in the nervous system

Haase

Pettmann

Raoul

et al. 2008

Current Opinion in Neurobiology

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SummaryCell death plays an important role both in shaping the developing nervous system and in neurological disease and traumatic injury. In spite of their name, death receptors can trigger either cell death or survival and growth. Recent studies implicate five death receptors -Fas/CD95, TNFR1 (tumor necrosis factor receptor-1), p75 NTR (p75 neurotrophin receptor), DR4 and DR5 (death receptors-4 and -5) -in different aspects of neural development or degeneration. Their roles may be neuroprotective in models of Parkinson's disease, or pro-apoptotic in ALS and stroke. Such different outcomes likely reflect the diversity of transcriptional and post-translational signaling pathways downstream of death receptors in neurons and glia.

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Activation of the p38MAPK cascade is associated with upregulation of TNF alpha receptors in the spinal motor neurons of mouse models of familial ALS

Cited by 93 publications

References 67 publications

Activation of the heat shock response in a primary cellular model of motoneuron neurodegeneration-evidence for neuroprotective and neurotoxic effects

Activation of the heat shock response in a primary cellular model of motoneuron neurodegeneration-evidence for neuroprotective and neurotoxic effects

Haploinsufficiency ofAFG3L2, the Gene Responsible for Spinocerebellar Ataxia Type 28, Causes Mitochondria-Mediated Purkinje Cell Dark Degeneration

Signaling by death receptors in the nervous system

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