Axonal loss in the pathology of MS: consequences for understanding the progressive phase of the disease

Bjartmar, Carl; Wujek, Jerome R.; Trapp, Bruce D.

doi:10.1016/s0022-510x(02)00069-2

Cited by 520 publications

(354 citation statements)

References 50 publications

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“…Lines of evidence suggest that some neurodegenerative diseases, such as Alzheimer's disease, multiple sclerosis and PD, are related to neural differentiation disorders [32][33][34] . The characteristics of PD are progressive degeneration of dopaminergic neurons in the substantia nigra of the midbrain and other brain regions, and visible intracellular inclusions, known as Lewy bodies [35] .…”

Section: Discussionmentioning

confidence: 99%

Protease Omi facilitates neurite outgrowth in mouse neuroblastoma N2a cells by cleaving transcription factor E2F1

et al. 2015

Acta Pharmacol Sin

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Aim:Omi is an ATP-independent serine protease that is necessary for neuronal function and survival. The aim of this study was to investigate the role of protease Omi in regulating differentiation of mouse neuroblastoma cells and to identify the substrate of Omi involved in this process. Methods: Mouse neuroblastoma N2a cells and Omi protease-deficient mnd2 mice were used in this study. To modulate Omi and E2F1 expression, N2a cells were transfected with expression plasmids, shRNA plasmids or siRNA. Protein levels were detected using immunoblot assays. The interaction between Omi and E2F1 was studied using immunoprecipitation, GST pulldown and in vitro cleavage assays. N2a cells were treated with 20 μmol/L retinoic acid (RA) and 1% fetal bovine serum to induce neurite outgrowth, which was measured using Image J software. Results: E2F1 was significantly increased in Omi knockdown cells and in brain lysates of mnd2 mice, and was decreased in cells overexpressing wild-type Omi, but not inactive Omi S276C. In brain lysates of mnd2 mice, endogenous E2F1 was co-immunoprecipitated with endogenous Omi. In vitro cleavage assay demonstrated that Omi directly cleaved E2F1. Treatment of N2a cells with RA induced marked differentiation and neurite outgrowth accompanied by significantly increased Omi and decreased E2F1 levels, which were suppressed by pretreatment with the specific Omi inhibitor UCF-101. Knockdown of Omi in N2a cells suppressed RA-induced neurite outgrowth, which was partially restored by knockdown of E2F1. Conclusion: Protease Omi facilitates neurite outgrowth by cleaving the transcription factor E2F1 in differentiated neuroblastoma cells; E2F1 is a substrate of Omi.

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Section: Discussionmentioning

confidence: 99%

Protease Omi facilitates neurite outgrowth in mouse neuroblastoma N2a cells by cleaving transcription factor E2F1

et al. 2015

Acta Pharmacol Sin

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“…It has become clear that many types of neurodegenerative diseases involve major synapse and axon losses before the appearance of symptoms, and even before the loss of neurons (Raff et al, 2002;Bjartmar et al, 2003;Saxena and Caroni, 2007). A variety of neurological disorders, including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, spinocerebellar disorders, peripheral neuropathies, nutritional neurological disorders, various intoxications and AIDS, are characterized by initial degeneration of the distal regions of long axons (Luo and O'Leary, 2005).…”

Section: Axon Degeneration Wld S and Neurodegenerative Diseasementioning

confidence: 99%

WldS, Nmnats and axon degeneration-progress in the past two decades

Yan

et al. 2010

Protein Cell

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A chimeric protein called Wallerian degeneration slow (Wld S ) was first discovered in a spontaneous mutant strain of mice that exhibited delayed Wallerian degeneration. This provides a useful tool in elucidating the mechanisms of axon degeneration. Over-expression of Wld S attenuates the axon degeneration that is associated with several neurodegenerative disease models, suggesting a new logic for developing a potential protective strategy. At molecular level, although Wld S is a fusion protein, the nicotinamide mononucleotide adenylyl transferase 1 (Nmnat1) is required and sufficient for the protective effects of Wld S , indicating a critical role of NAD biosynthesis and perhaps energy metabolism in axon degeneration. These findings challenge the proposed model in which axon degeneration is operated by an active programmed process and thus may have important implication in understanding the mechanisms of neurodegeneration. In this review, we will summarize these recent findings and discuss their relevance to the mechanisms of axon degeneration.

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“…2,26,101 This is beginning to underscore the new belief that the major cause of permanent progressive disability is because of neurodegeneration. 102,103 While this occurs early in MS and EAE, 102,103 it is likely that because of inflammationinduced demyelination, a CNS microenvironment is created where the nerves are particularly sensitive to neurotoxic insults, such as glutamate excitotoxcity, oxidative free-radical damage and toxic ion fluxes, and a slow degenerative process that may continue independent of the inflammatory response is triggered. 102,[104][105][106][107] Although some success has been shown by genedelivered growth factors that provide trophic support (eg NGF and PDGF.…”

Section: Future Prospects For Gene Therapy In Cns Autoimmune Demyelinmentioning

confidence: 99%

“…102,103 While this occurs early in MS and EAE, 102,103 it is likely that because of inflammationinduced demyelination, a CNS microenvironment is created where the nerves are particularly sensitive to neurotoxic insults, such as glutamate excitotoxcity, oxidative free-radical damage and toxic ion fluxes, and a slow degenerative process that may continue independent of the inflammatory response is triggered. 102,[104][105][106][107] Although some success has been shown by genedelivered growth factors that provide trophic support (eg NGF and PDGF. Table 1), 49,57 neuroprotection by any route in CNS autoimmunity, particularly in long-established disease, is essentially unexplored.…”

Section: Future Prospects For Gene Therapy In Cns Autoimmune Demyelinmentioning

confidence: 99%

Gene therapy in autoimmune, demyelinating disease of the central nervous system

Baker

Hankey

2003

Gene Ther

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Axonal loss in the pathology of MS: consequences for understanding the progressive phase of the disease

Cited by 520 publications

References 50 publications

Protease Omi facilitates neurite outgrowth in mouse neuroblastoma N2a cells by cleaving transcription factor E2F1

Protease Omi facilitates neurite outgrowth in mouse neuroblastoma N2a cells by cleaving transcription factor E2F1

WldS, Nmnats and axon degeneration-progress in the past two decades

Gene therapy in autoimmune, demyelinating disease of the central nervous system

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