Lack of involvement of neuronal nitric oxide synthase in the pathogenesis of a transgenic mouse model of familial amyotrophic lateral sclerosis

Facchinetti, Fabrizio; Sasaki, Masayuki; Fb, Cutting; Zhai, Ping; Je, MacDonald; Reif, David W.; Mf, Beal; Huang, Paul L.; Dawson, T. Renee; Me, Gurney; Dawson, VL

doi:10.1016/s0306-4522(98)00492-8

Cited by 81 publications

(38 citation statements)

References 64 publications

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“…The nNOS mutant mice used for the cross display residual NOS activity of Ϸ15% of control and, strikingly, produce the same ␤ and ␥ forms of nNOS as those found in ALS patients (32). In support of our model, administration of the nNOS inhibitor AR-R 17.477 significantly prolonged the lifespan of SOD1 G93A mutant mice (32). In the future, it will be important to determine the precise role of NO synthases in this process, because a requirement for NO also has been demonstrated in death of motoneurons induced by avulsion (35) or neurofilament gene mutations (36).…”

Section: Discussionmentioning

confidence: 79%

“…Nevertheless, the nNOS enzyme can exist in three forms resulting from alternative splicing (33) and specific increases in the ␤ and ␥ forms have been reported in spinal cords from sporadic ALS patients (34). The nNOS mutant mice used for the cross display residual NOS activity of Ϸ15% of control and, strikingly, produce the same ␤ and ␥ forms of nNOS as those found in ALS patients (32). In support of our model, administration of the nNOS inhibitor AR-R 17.477 significantly prolonged the lifespan of SOD1 G93A mutant mice (32).…”

Section: Discussionmentioning

confidence: 98%

“…In the past, crossing mutant SOD1 mice with mice carrying a loss-of-function allele of the nNOS gene did not prolong survival (32). Nevertheless, the nNOS enzyme can exist in three forms resulting from alternative splicing (33) and specific increases in the ␤ and ␥ forms have been reported in spinal cords from sporadic ALS patients (34).…”

Section: Discussionmentioning

confidence: 99%

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Chronic activation in presymptomatic amyotrophic lateral sclerosis (ALS) mice of a feedback loop involving Fas, Daxx, and FasL

Raoul

Buhler

Sadeghi

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

100

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The reasons for the cellular specificity and slow progression of motoneuron diseases such as ALS are still poorly understood. We previously described a motoneuron-specific cell death pathway downstream of the Fas death receptor, in which synthesis of nitric oxide (NO) is an obligate step. Motoneurons from ALS model mice expressing mutant SOD1 showed increased susceptibility to exogenous NO as compared with controls. Here, we report a signaling mechanism whereby NO leads to death of mutant, but not control, motoneurons. Unexpectedly, exogenous NO triggers expression of Fas ligand (FasL) in cultured motoneurons. In mutant SOD1 G93A and SOD1 G85R , but not in control motoneurons, this up-regulation results in activation of Fas, leading through Daxx to phosphorylation of p38 and further NO synthesis. This Fas͞NO feedback amplification loop is required for motoneuron death in vitro. In vivo, mutant SOD1 G93A and SOD1 G85R mice show increased numbers of positive motoneurons and Daxx nuclear bodies weeks before disease onset. Moreover, FasL up-regulation is reduced in the presence of transgenic dominant-negative Daxx. We propose that chronic low-level activation of the Fas͞NO feedback loop may underlie the motoneuron loss that characterizes familial ALS and may help to explain its slowly progressive nature.cell death ͉ motoneuron disease ͉ NO ͉ p38 kinase ͉ neurodegeneration A myotrophic lateral sclerosis (ALS) is the most frequent adultonset motoneuron disease in humans. ALS is characterized by the selective degeneration of motoneurons in spinal cord, brainstem, and cerebral cortex leading to muscle atrophy and paralysis and ultimately to death. About 1 to 2% of all human ALS forms are caused by dominantly inherited mutations in the Cu͞Zn superoxide dismutase (SOD1) gene. Mice transgenic for the ALS-linked SOD1 mutations G37R (1), H46R͞H48Q (2), G85R (3), and G93A (4) develop an adult-onset motoneuron disorder that remarkably resembles human ALS.Despite much intensive study, many questions remain concerning the mechanism(s) by which mutant SOD1 triggers specific motoneuron death. One unresolved issue is the cellular site of action of the gain-of-function mutations. Clement et al. (5) generated chimeric mice carrying a mixture of WT and mutant SOD1-expressing cells in the spinal cord. In these mice, WT motoneurons eventually showed stigmata of degeneration, whereas some mutant SOD1 motoneurons were protected from degeneration when surrounded by WT nonneuronal cells. These results suggest that mutant SOD1 in both motoneurons and surrounding cells may play a role in the disease process.Our earlier studies using cultures of purified embryonic motoneurons reached similar conclusions. We found that motoneurons from SOD1 G93A , SOD1 G37R , and SOD1 G85R mice survived normally in the presence of optimal trophic support or when challenged by excitotoxic agonists. In marked contrast, compared with controls, they displayed a 10-to 100-fold increase in sensitivity to extracellular agonists of the Fas receptor or to exogenous nitr...

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 98%

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Chronic activation in presymptomatic amyotrophic lateral sclerosis (ALS) mice of a feedback loop involving Fas, Daxx, and FasL

Raoul

Buhler

Sadeghi

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

100

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“…The toxicity was attributed to an anomalous backward conversion of oxygen to superoxide in the Zn-depleted active site, and the superoxide subsequently combined with nitric oxide to form toxic peroxynitrite (43,44). However, peroxynitritemediated toxicity has gained little support from studies in transgenic mice (45), because termination of the neuronal nitric oxide synthase does not attenuate the disease (46). A toxicity pathway of Zn-free SOD based on increased accumulation of the apo species could perhaps reconcile these data.…”

Section: Discussionmentioning

confidence: 99%

Common denominator of Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis: Decreased stability of the apo state

Lindberg

Tibell

Oliveberg

2002

Proc. Natl. Acad. Sci. U.S.A.

183

177

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More than 100 point mutations of the superoxide scavenger Cu͞Zn superoxide dismutase (SOD; EC 1.15.1.1) have been associated with the neurodegenerative disease amyotrophic lateral sclerosis (ALS). However, these mutations are scattered throughout the protein and provide no clear functional or structural clues to the underlying disease mechanism. Therefore, we undertook to look for foldingrelated defects by comparing the unfolding behavior of five ALS-associated mutants with distinct structural characteristics: A4V at the interface between the N and C termini, C6F in the hydrophobic core, D90A at the protein surface, and G93A and G93C, which decrease backbone flexibility. With the exception of the disruptive replacements A4V and C6F, the mutations only marginally affect the stability of the native protein, yet all mutants share a pronounced destabilization of the metal-free apo state: the higher the stability loss, the lower the mean survival time for ALS patients carrying the mutation. Thus organism-level pathology may be directly related to the properties of the immature state of a protein rather than to those of the native species.A myotrophic lateral sclerosis (ALS) is a motor neuron syndrome where a sub group of 3-6% has been associated with a diverse set of mutations in the superoxide scavenger Cu͞Zn superoxide dismutase (SOD; 1.15.1.1) (1, 2). Interestingly, several of these mutations show perfectly native-like in vivo activity (3, 4) and metal coordination (5). As an alternative cause of disease, transgenic mouse models suggest that ALS arises through an adverse, and yet-unidentified, side reaction of the mutated protein causing cytotoxicity. Mice devoid of SOD retain normal motor function (6), as do mice overexpressing wild-type SOD. In contrast, mice expressing high levels of mutant human SOD in addition to endogenous SOD show neural damage. The collective evidence suggests that mutant SOD has gained a cytopathogenic function (7,8). Models for how the neurodegenerating toxicity arise include the following: (i) enzymatic side-reactions in catalytically promiscuous SOD mutants producing increased levels of oxidative compounds such as hydroxyl radicals (9-11) and peroxynitrite (12), (ii) release of free Cu ions (13), (iii) aberrant binding of SOD to other proteins (14), (iv) binding of mutant SOD to heat shock proteins (15, 16) with the subsequent prevention of their antiapoptotic function (16), (v) altered redox regulation (17), and (vi) formation of toxic SOD aggregates (18)(19)(20). Evidence that could potentially distinguish between these models was recently provided from mice lacking the metal-loading chaperone CCS (copper chaperone for SOD; ref. 21). The chaperone is essential for incorporating the copper ion and, hence, to gain the native protein. When the CCS gene was ablated, the ALS-associated mutations were observed to still provoke the disease, indicating that a copper-free precursor state of SOD causes neurotoxicity (21). Along this line, a broad spectrum of mechanistic scenarios is implicated...

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“…Astrocytes of mutant SOD1 mice and ALS patients exhibit increased levels of NOS, 13 inhibition of NOS prevents motor neuron loss, 23 and at least one NOS inhibitor prolongs the life span of SOD1 mutant mice. 24 In addition, astrocyte production of NO or ONOO À induces mitochondrial injury 25,26 and motor neuron apoptosis requires astrocyte production of NO. 27 ALS patients, mutant SOD1 mice, and motor neurons undergoing apoptosis, all exhibit increased levels of nitrotyrosine, the nitration of tyrosine residues by ONOO À altering cellular proteins.…”

Section: Astrocytes: Poisonous Neighborsmentioning

confidence: 99%

ALS: astrocytes take center stage, but must they share the spotlight?

Knott

Bossy‐Wetzel

2007

Cell Death Differ

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Lack of involvement of neuronal nitric oxide synthase in the pathogenesis of a transgenic mouse model of familial amyotrophic lateral sclerosis

Cited by 81 publications

References 64 publications

Chronic activation in presymptomatic amyotrophic lateral sclerosis (ALS) mice of a feedback loop involving Fas, Daxx, and FasL

Chronic activation in presymptomatic amyotrophic lateral sclerosis (ALS) mice of a feedback loop involving Fas, Daxx, and FasL

Common denominator of Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis: Decreased stability of the apo state

ALS: astrocytes take center stage, but must they share the spotlight?

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