A role for astrocytes in motor neuron loss in amyotrophic lateral sclerosis

Barbeito, Luis; Pehar, Mariana; Cassina, Patricia; Vargas, Marcelo R.; Peluffo, Hugo; Viera, Liliana; Estévez, Álvaro G.; Beckman, Joseph S.

doi:10.1016/j.brainresrev.2004.05.003

Cited by 282 publications

(240 citation statements)

References 135 publications

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“…Findings from SOD1 transgenic mice support a role for astrogliosis in the pathology of familial ALS. However, this area is controversial in terms of when astrogliosis occurs and whether it precedes or accompanies dysfunction of motoneurons (Barbeito et al, 2004;Boillee et al, 2006;Maragakis and Rothstein, 2006). Although motoneurons were intact histologically and physiologically when there was marked astrogliosis with loss of EAAT2 in the SOD1 mutant rat model of ALS (Howland et al, 2002), other studies do not show a presymptomatic loss of EAAT2 (Bendotti et al, 2001;Dunlop et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Oxidative mediators chosen were based on their relevance to ALS: 3-morpholinosydnonimine chloride (SIN-1; Barbeito et al, 2004;Trotti et al, 1996), trans-4-hydroxy-2-nonenal (4-HNE; Blanc et al, 1998;Keller et al, 1997;Pedersen et al, 1998Pedersen et al, , 1999 and hydrogen peroxide (H 2 O 2 ; Gurney et al, 1998). For comparison, an excitotoxic insult with the potent AMPA receptor agonist, (S)-5-fluorowillardiine (FW; Patneau et al, 1992), was chosen based on the AMPA receptor-mediated calcium permeability of motoneurons (Greig et al, 2000;Van Den Bosch et al, 2000), which makes them susceptible to excitotoxicity.…”

Section: Drug Treatmentsmentioning

confidence: 99%

“…Although the loss of motoneurons is the direct cause of motor symptoms, the noncell-autonomous hypothesis of ALS attributes a role to non-neuronal cells in disease etiology (Boillee et al, 2006). In particular, reactive astrogliosis, characterized by astrocytes with hypertrophic processes and increased expression of glial fibrillary acidic protein (GFAP; Pekny and Nilsson, 2005), combined with dysfunctional excitatory amino acid transporters (EAATs), are well documented in both humans and in rodent models of ALS (Barbeito et al, 2004;Boillee et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Oxidative and excitotoxic insults exert differential effects on spinal motoneurons and astrocytic glutamate transporters: Implications for the role of astrogliosis in amyotrophic lateral sclerosis

Zagami

Beart

Wallis

et al. 2008

Glia

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In amyotrophic lateral sclerosis (ALS) non-neuronal cells play key roles in disease etiology and loss of motoneurons via noncell-autonomous mechanisms. Reactive astrogliosis and dysfunctional transporters for L-glutamate [excitatory amino acid transporters, (EAATs)] are hallmarks of ALS pathology. Here, we describe mechanistic insights into ALS pathology involving EAAT-associated homeostasis in response to a destructive milieu, in which oxidative stress and excitotoxicity induce respectively astrogliosis and motoneuron injury. Using an in vitro neuronal-glial culture of embryonic mouse spinal cord, we demonstrate that EAAT activity was maintained initially, despite a loss of cellular viability induced by exposure to oxidative [3-morpholinosydnonimine chloride (SIN-1)] and excitotoxic [(S)-5-fluorowillardiine (FW)] conditions. This homeostatic response of EAAT function involved no change in the cell surface expression of EAAT1/2 at 0.5-4 h, but rather alterations in kinetic properties. Over this time-frame, EAAT1/2 both became more widespread across astrocytic arbors in concert with increased expression of glial fibrillary acidic protein (GFAP), although at 8-24 h there was gliotoxicity, especially with SIN-1 rather than FW. An opposite picture was found for motoneurons where FW, not SIN-1, produced early and extensive neuritic shrinkage and blebbing ( 0.5 h) with somata loss from 2 h. We postulate that EAATs play an early homeostatic and protective role in the pathologic milieu. Moreover, the differential profiles of injury produced by oxidative and excitotoxic insults identify two distinct phases of injury which parallel important aspects of the pathology of ALS. V V C

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Section: Discussionmentioning

confidence: 99%

Section: Drug Treatmentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Oxidative and excitotoxic insults exert differential effects on spinal motoneurons and astrocytic glutamate transporters: Implications for the role of astrogliosis in amyotrophic lateral sclerosis

Zagami

Beart

Wallis

et al. 2008

Glia

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“…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. 23 Taken together, these findings create the possibility that NO is one of the factors that diffuses from mutant SOD1 astrocytes to trigger neighboring motor neuron cell death. Selective destruction of motor neurons triggered by NO is plausible and would coincide with the results of the Nagai et al study.…”

Section: Astrocytes: Poisonous Neighborsmentioning

confidence: 95%

“…However, when produced in excess, NO combines with superoxide anions (O 2 À ) to form ONOO À , which is a highly neurotoxic radical. 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.…”

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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Assessing neuraxial microstructural changes in a transgenic mouse model of early stage Amyotrophic Lateral Sclerosis by ultra‐high field MRI and diffusion tensor metrics

Gatto

Weissmann

Amin

et al. 2020

Anim Models and Exp Med

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ObjectiveCell structural changes are one of the main features observed during the development of amyotrophic lateral sclerosis (ALS). In this work, we propose the use of diffusion tensor imaging (DTI) metrics to assess specific ultrastructural changes in the central nervous system during the early neurodegenerative stages of ALS.MethodsUltra‐high field MRI and DTI data at 17.6T were obtained from fixed, excised mouse brains, and spinal cords from ALS (G93A‐SOD1) mice.ResultsChanges in fractional anisotropy (FA) and linear, planar, and spherical anisotropy ratios (CL, CP, and CS, respectively) of the diffusion eigenvalues were measured in white matter (WM) and gray matter (GM) areas associated with early axonal degenerative processes (in both the brain and the spinal cord). Specifically, in WM structures (corpus callosum, corticospinal tract, and spinal cord funiculi) as the disease progressed, FA, CL, and CP values decreased, whereas CS values increased. In GM structures (prefrontal cortex, hippocampus, and central spinal cord) FA and CP decreased, whereas the CL and CS values were unchanged or slightly smaller. Histological studies of a fluorescent mice model (YFP, G93A‐SOD1 mouse) corroborated the early alterations in neuronal morphology and axonal connectivity measured by DTI.ConclusionsChanges in diffusion tensor shape were observed in this animal model at the early, nonsymptomatic stages of ALS. Further studies of CL, CP, and CS as imaging biomarkers should be undertaken to refine this neuroimaging tool for future clinical use in the detection of the early stages of ALS.

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A role for astrocytes in motor neuron loss in amyotrophic lateral sclerosis

Cited by 282 publications

References 135 publications

Oxidative and excitotoxic insults exert differential effects on spinal motoneurons and astrocytic glutamate transporters: Implications for the role of astrogliosis in amyotrophic lateral sclerosis

Oxidative and excitotoxic insults exert differential effects on spinal motoneurons and astrocytic glutamate transporters: Implications for the role of astrogliosis in amyotrophic lateral sclerosis

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

Assessing neuraxial microstructural changes in a transgenic mouse model of early stage Amyotrophic Lateral Sclerosis by ultra‐high field MRI and diffusion tensor metrics

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