Evidence that accumulation of ceramides and cholesterol esters mediates oxidative stress–induced death of motor neurons in amyotrophic lateral sclerosis

Cutler, Roy G.; Pedersen, Ward A.; Camandola, Simonetta; Rothstein, Jeffrey D.; Mattson, Mark P.

doi:10.1002/ana.10312

Cited by 255 publications

(239 citation statements)

References 52 publications

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“…In contrast, our analysis of cervical spinal cord gray and white matter samples showed that the major isoforms of Cer, GalCer, GlcCer, LacCer, GM3, GM1, GL3, and SPM were significantly elevated in ALS patients. These findings corroborate an earlier study that evaluated Cer and SPM levels in human ALS spinal cords (29). Importantly, we also showed that GSL-related pathology in ALS patients was not due to a reduction in the activity of the enzymes that mediate their degradation (as is observed in lysosomal storage diseases); acidic enzymatic activities of GBA1, GBA2, HEX, GALC, α-GAL, and β-GAL were all significantly increased in ALS spinal cord samples.…”

Section: Discussionsupporting

confidence: 92%

Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis

Dodge

Treleaven

Pacheco

et al. 2015

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

107

134

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Recent genetic evidence suggests that aberrant glycosphingolipid metabolism plays an important role in several neuromuscular diseases including hereditary spastic paraplegia, hereditary sensory neuropathy type 1, and non-5q spinal muscular atrophy. Here, we investigated whether altered glycosphingolipid metabolism is a modulator of disease course in amyotrophic lateral sclerosis (ALS). Levels of ceramide, glucosylceramide, galactocerebroside, lactosylceramide, globotriaosylceramide, and the gangliosides GM3 and GM1 were significantly elevated in spinal cords of ALS patients. Moreover, enzyme activities (glucocerebrosidase-1, glucocerebrosidase-2, hexosaminidase, galactosylceramidase, α-galactosidase, and β-galactosidase) mediating glycosphingolipid hydrolysis were also elevated up to threefold. Increased ceramide, glucosylceramide, GM3, and hexosaminidase activity were also found in SOD1 G93A mice, a familial model of ALS. Inhibition of glucosylceramide synthesis accelerated disease course in SOD1 G93A mice, whereas infusion of exogenous GM3 significantly slowed the onset of paralysis and increased survival. Our results suggest that glycosphingolipids are likely important participants in pathogenesis of ALS and merit further analysis as potential drug targets.A myotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by selective loss of motor neurons (MNs) within the CNS. Although our understanding of the genetic basis of ALS has advanced greatly in recent years (1), the adverse biological processes that converge on the neuromuscular axis to drive both MN death and neuropathological features in additional cell types remain largely unknown. Glycosphingolipids (GSLs) are a heterogeneous group of membrane lipids formed through the covalent linkage of a glycan moiety to ceramide (Cer; see SI Appendix, Fig. S1 for an overview of GSL metabolism). Glucosylceramide (GlcCer) and galactosylceramide (GalCer) are GSLs with a single sugar residue: glucose and galactose respectively. The successive addition of galactose and sialic acid moieties to GlcCer results in the synthesis of gangliosides (e.g., GM3, GM2, and GM1) (2). GSLs are especially abundant in the CNS and have bioactive roles in metabolism, growth factor signaling, oligodendrocyte differentiation, neuroinflammation, angiogenesis, and pathways of cell death (2-9)-all of which are thought to participate in ALS disease pathogenesis.Several lines of evidence suggest that aberrant changes in GSL homeostasis may contribute to disease pathogenesis in ALS. Evidence includes the detection of unique gangliosides (10), high titer serum auto-antibodies to GM2 and GM1 (11,12), and elevated GM2 levels within the motor cortex of ALS patients (13). Furthermore, a number of neuromuscular diseases are associated with mutations in genes that regulate the metabolism of Cer and GSLs. For example, hereditary sensory neuropathy type I (HSNT1), a disease that features dorsal root ganglion cell and MN degeneration, is attributed to mutations in serine...

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Section: Discussionsupporting

confidence: 92%

Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis

Dodge

Treleaven

Pacheco

et al. 2015

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

107

134

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“…The homogenate was centrifuged at 1,000 ϫ g for 15 min at 4°C and the nuclear pellet was washed one time and then discarded. The combined original and wash supernatants were centrifuged at 100,000 ϫ g for 1 h and the resulting crude membrane pellet was quick-frozen and stored at 4 C. Before lipid extraction, the membrane samples were normalized based on an average wet weight of Ϸ19 mg. Electrospray tandem MS analyses were performed by using methods described (16).…”

Section: Methodsmentioning

confidence: 99%

Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease

Cutler

Kelly

Storie

et al. 2004

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

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972

816

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Alzheimer's disease (AD) is an age-related disorder characterized by deposition of amyloid ␤-peptide (A␤) and degeneration of neurons in brain regions such as the hippocampus, resulting in progressive cognitive dysfunction. The pathogenesis of AD is tightly linked to A␤ deposition and oxidative stress, but it remains unclear as to how these factors result in neuronal dysfunction and death. We report alterations in sphingolipid and cholesterol metabolism during normal brain aging and in the brains of AD patients that result in accumulation of long-chain ceramides and cholesterol. Membrane-associated oxidative stress occurs in association with the lipid alterations, and exposure of hippocampal neurons to A␤ induces membrane oxidative stress and the accumulation of ceramide species and cholesterol. Treatment of neurons with ␣-tocopherol or an inhibitor of sphingomyelin synthesis prevents accumulation of ceramides and cholesterol and protects them against death induced by A␤. Our findings suggest a sequence of events in the pathogenesis of AD in which A␤ induces membrane-associated oxidative stress, resulting in perturbed ceramide and cholesterol metabolism which, in turn, triggers a neurodegenerative cascade that leads to clinical disease.amyloid ͉ apoptosis ͉ hippocampus ͉ lipid peroxidation ͉ sphingomyelin C hanges that occur in the brain during aging increase the risk of Alzheimer's disease (AD), a disorder involving the progressive deposition of amyloid ␤-peptide (A␤) and associated degeneration of neurons in brain regions involved in learning and memory (1). Two factors that are believed to contribute to neuronal dysfunction and degeneration in AD are increased oxidative stress and increased production of neurotoxic forms of A␤ (2). Alterations in lipid metabolism may also play roles in AD because the risk of AD is affected by inheritance of different isoforms of apolipoprotein E (3), changes in cholesterol metabolism can affect A␤ production in cell culture and in vivo (4-6), and drugs that lower cholesterol levels may reduce the risk of AD (7,8). However, a direct link between alterations in the metabolism of cholesterol and other membrane lipids in AD has not been established, and it is not known whether and how such lipid alterations might lead to neuronal dysfunction and death.Membrane microdomains that are rich in cholesterol and sphingolipids play important roles in various cellular signaling pathways (9, 10). Sphingomyelin is a major source of ceramides, lipid mediators that are generated when sphingomyelin is cleaved by sphingomyelinases, enzymes activated by inflammatory cytokines (11) and oxidative stress (12). Ceramides play important roles in regulating an array of physiological processes, including cell proliferation and differentiation, and a form of programmed cell death called apoptosis (13). Ceramides have been implicated in the pathological death of neurons that occurs in ischemic stroke (14) and Parkinson's disease (15). In the present study, we document significant increases in levels of m...

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“…Thus, it seems that p75 NTR is able to activate different SMases depending on the cell type. Interestingly, the spinal cord of ALS patients and SOD1 G93A mice exhibit a remarkable increase in ceramides and cholesterol esters, which have been shown to sensitize motor neurons to different death stimuli including oxidative and excitotoxic insults (Cutler et al, 2002). Therefore, NGF signaling through p75 NTR and the subsequent increase in ceramide production may also modulate the sensitivity of motor neurons to other apoptotic stimuli.…”

Section: Reexpression Of P75mentioning

confidence: 99%

Mitochondrial Superoxide Production and Nuclear Factor Erythroid 2-Related Factor 2 Activation in p75 Neurotrophin Receptor-Induced Motor Neuron Apoptosis

Pehar

Vargas²,

Robinson³

et al. 2007

J. Neurosci.

109

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Nerve growth factor (NGF) can induce apoptosis by signaling through the p75 neurotrophin receptor (p75 NTR ) in several nerve cell populations. Cultured embryonic motor neurons expressing p75 NTR are not vulnerable to NGF unless they are exposed to an exogenous flux of nitric oxide ( ⅐ NO). In the present study, we show that p75 NTR -mediated apoptosis in motor neurons involved neutral sphingomyelinase activation, increased mitochondrial superoxide production, and cytochrome c release to the cytosol. The mitochondria-targeted antioxidants mitoQ and mitoCP prevented neuronal loss, further evidencing the role of mitochondria in NGF-induced apoptosis. In motor neurons overexpressing the amyotrophic lateral sclerosis (ALS)-linked superoxide dismutase 1 G93A (SOD1 G93A ) mutation, NGF induced apoptosis even in the absence of an external source of ⅐ NO. The increased susceptibility of SOD1 G93A motor neurons to NGF was associated to decreased nuclear factor erythroid 2-related factor 2 (Nrf2) expression and downregulation of the enzymes involved in glutathione biosynthesis. In agreement, depletion of glutathione in nontransgenic motor neurons reproduced the effect of SOD1 G93A expression, increasing their sensitivity to NGF. In contrast, rising antioxidant defenses by Nrf2 activation prevented NGF-induced apoptosis. Together, our data indicate that p75 NTR -mediated motor neuron apoptosis involves ceramide-dependent increased mitochondrial superoxide production. This apoptotic pathway is facilitated by the expression of ALS-linked SOD1 mutations and critically modulated by Nrf2 activity.

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Evidence that accumulation of ceramides and cholesterol esters mediates oxidative stress–induced death of motor neurons in amyotrophic lateral sclerosis

Cited by 255 publications

References 52 publications

Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis

Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis

Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease

Mitochondrial Superoxide Production and Nuclear Factor Erythroid 2-Related Factor 2 Activation in p75 Neurotrophin Receptor-Induced Motor Neuron Apoptosis

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