Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis

Kang, Shin-Hyoung; Liu, Ying; Fukaya, Masahiro; Lorenzini, Ileana; Cleveland, Don W.; Ostrow, Lyle W.; Rothstein, Jeffrey D.; Bergles, Dwight E.

doi:10.1038/nn.3357

Cited by 506 publications

(621 citation statements)

References 53 publications

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“…Finally, an involvement of ventral gray matter oligodendrocytes in pathogenesis of SOD1-linked ALS is supported by several recent studies (34)(35)(36). Both early-onset turnover of mature oligodendrocytes themselves, with activated precursor proliferation/differentiation, and toxicity conferred by dysfunctional oligodendrocytes upon motor neurons were reported.…”

Section: Discussionmentioning

confidence: 57%

“…Both early-onset turnover of mature oligodendrocytes themselves, with activated precursor proliferation/differentiation, and toxicity conferred by dysfunctional oligodendrocytes upon motor neurons were reported. Reduction of SOD1 in oligodendrocytes was able to delay onset of SOD1-linked ALS in a transgenic mouse strain (34). The finding here of transfer of mutant SOD1 and putatively other cytosolic proteins to oligodendrocytes, and the potential of oligodendrocytes to transfer cytosolic proteins to motor neurons could add a further level of understanding to these observations.…”

Section: Discussionmentioning

confidence: 58%

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Transfer of pathogenic and nonpathogenic cytosolic proteins between spinal cord motor neurons in vivo in chimeric mice

Thomas

Fenton

McGrath

et al. 2017

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

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Recent studies have reported spread of pathogenic proteins in the mammalian nervous system, but whether nonpathogenic ones spread is unknown. We initially investigated whether spread of a mutant amyotrophic lateral sclerosis-associated cytosolic superoxide dismutase 1 (SOD1) protein between motor neurons could be detected in intact chimeric mice. Eight-cell embryos from G85R SOD1YFP and G85R SOD1CFP mice were aggregated, and spinal cords of adult chimeric progeny were examined for motor neurons with cytosolic double fluorescence. By 3 mo of age, we observed extensive double fluorescence, including in amyotrophic lateral sclerosisaffected cranial nerve motor nuclei but not in the relatively spared extraocular nuclei. Chimeras of nonpathogenic wtSOD1YFP and G85R SOD1CFP also exhibited double fluorescence. In a third chimera, mitochondrial mCherry did not transfer to G85R SOD1YFP motor neurons, suggesting that neither RNA nor organelles transfer, but mitomCherry neurons received G85R SOD1YFP. In a chimera of ChAT promoter-EGFP and mito-mCherry, EGFP efficiently transferred to mito-mCherry + cells. Thus, nonpathogenic cytosolic proteins appear capable of transfer. During study of both the SOD1FP and EGFP chimeras, we observed fluorescence also in small cells neighboring the motor neurons, identified as mature gray matter oligodendrocytes. Double fluorescence in the G85R SOD1FP chimera and observation of the temporal development of fluorescence first in motor neurons and then in these oligodendrocytes suggest that they may be mediators of transfer of cytosolic proteins between motor neurons.

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 58%

Transfer of pathogenic and nonpathogenic cytosolic proteins between spinal cord motor neurons in vivo in chimeric mice

Thomas

Fenton

McGrath

et al. 2017

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

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“…patients and SOD1 G93A mice. An increase in GM3 may also potentially slow disease by promoting oligodendrocyte differentiation (6), which is adversely affected in ALS mice (37), or by inhibiting the activation of matrix metalloproteinase-9 (38), which is expressed at high levels in those MNs most vulnerable in ALS (39). Interestingly, gene expression analysis studies carried out in ALS mice have shown that HEX (an enzyme that metabolizes GM2 to GM3) mRNA level is up-regulated in MNs before and during overt signs of disease (21,22).…”

Section: Discussionmentioning

confidence: 99%

Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis

Dodge

Treleaven

Pacheco

et al. 2015

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

109

141

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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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“…1). The Mouse Cell Cycle RT 2 Profiler TM PCR Arrays containing 86 probe sets that both positively and negatively regulate the cell cycle, the transitions between each of the phases, DNA replication, checkpoints and arrest were used. Of those, only probe sets with a difference of 1.2 folds or above in expression levels, and a p-value less than 0.05 between control and CPZ groups were used for further analysis.…”

Section: Cpz Administration Upregulated the Expression Of Cell Cyclementioning

confidence: 99%

“…Malfunction of oligodendrocyte development and demyelination have been considered as a pathological substrate for cognitive dysfunction inmultiple sclerosis (MS) and schizophrenia. 1,2 Therefore, identifying and manipulating the factors regulating oligodendrocyteprecursor cells (OPCs) proliferation and differentiation are crucial to the elucidation of pathological mechanisms of demyelination diseases.…”

Section: Introductionmentioning

confidence: 99%

Cyclin-dependent kinase inhibitor flavopiridol promotes remyelination in a cuprizone induced demyelination model

Mi¹,

Gao

Liu³

et al. 2016

Cell Cycle

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The cuprizone (CPZ) model has been widely used for the studies of de-and remyelination. The CPZexposed mice show oligodendrocyte precursor cells (OPCs) increase and mature oligodendrocytes decrease, suggesting an imbalance between proliferation and differentiation of OPCs. In the first experiment of this study, we examined the expression of cell cycle related genes in brains of mice following CPZ administration for 5 weeks by means of microarray assay. In addition, we performed a double labeling of BrdU and Ki-67 to calculate cell cycle exit index in the mice. Our results showed that CPZ administration up-regulated the expression of 16 cell cycle related genes, but down-regulated the expression of only one in the prefrontal cortex (PFC) of mice compared to control group. The treatment inhibited potential precursor cells exit from cell cycle. In the second experiment, we evaluated effects of a CDK inhibitor flavopiridol (FLA) on CPZ-induced neuropathological changes and spatial working memory impairment in mice.FLA treatment for one week effectively attenuated the CPZ-induced increases in NG2 positive cells, microglia and astrocytes, alleviated the concurrent mature oligodendrocyte loss and myelin breakdown, and improved spatial working memory deficit in the CPZ-exposed mice. These results suggest that CPZ-induced neuropathological changes involve in dysregulation of cell cycle related genes. The therapeutic effects of FLA on CPZ-exposed mice may be related to its ability of cell cycle inhibition.

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Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis

Cited by 506 publications

References 53 publications

Transfer of pathogenic and nonpathogenic cytosolic proteins between spinal cord motor neurons in vivo in chimeric mice

Transfer of pathogenic and nonpathogenic cytosolic proteins between spinal cord motor neurons in vivo in chimeric mice

Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis

Cyclin-dependent kinase inhibitor flavopiridol promotes remyelination in a cuprizone induced demyelination model

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