Accumulation of galactosylsphingosine (psychosine) does not interfere with phosphorylation and methylation of myelin basic protein in the twitcher mouse

Yoshimura, Teizo; Kobayashi, Takuro; Shinnoh, Nobue; Goto, Ikuo

doi:10.1007/bf00965740

Cited by 6 publications

(2 citation statements)

References 45 publications

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“…Extensive dysmyelination and axonal loss is present in the twi-5J sciatic nerve by P25, yet psychosine levels are substantially lower than measured or reported for twitcher at a comparable age ( 46 versus 158 pmol/mg protein) (41), underscoring the finding that axonal and myelin pathology do not correlate with tissue psychosine levels. This is consistent with the observation that psychosine is unable to induce Schwann cell death in twitcher animals in vivo (3,42). Like twitcher and twi-5J, infantile Krabbe patients exhibit higher levels of psychosine accumulation in the brainstem and spinal cord compared with the cortex (1,43).…”

Section: Discussionsupporting

confidence: 87%

Missense mutation in mouse GALC mimics human gene defect and offers new insights into Krabbe disease

Potter¹,

Santos²,

Davisson³

et al. 2013

Human Molecular Genetics

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Krabbe disease is a devastating pediatric leukodystrophy caused by mutations in the galactocerebrosidase (GALC) gene. A significant subset of the infantile form of the disease is due to missense mutations that result in aberrant protein production. The currently used mouse model, twitcher, has a nonsense mutation not found in Krabbe patients, although it is similar to the human 30 kb deletion in abrogating GALC expression. Here, we identify a spontaneous mutation in GALC, GALCtwi-5J, that precisely matches the E130K missense mutation in patients with infantile Krabbe disease. GALCtwi-5J homozygotes show loss of enzymatic activity despite normal levels of precursor protein, and manifest a more severe phenotype than twitcher, with half the life span. Although neuropathological hallmarks such as gliosis, globoid cells and psychosine accumulation are present throughout the nervous system, the CNS does not manifest significant demyelination. In contrast, the PNS is severely hypomyelinated and lacks large diameter axons, suggesting primary dysmyelination, rather than a demyelinating process. Our data indicate that early demise is due to mechanisms other than myelin loss and support an important role for neuroinflammation in Krabbe disease progression. Furthermore, our results argue against a causative relationship between psychosine accumulation, white matter loss and gliosis.

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Section: Discussionsupporting

confidence: 87%

Missense mutation in mouse GALC mimics human gene defect and offers new insights into Krabbe disease

Potter¹,

Santos²,

Davisson³

et al. 2013

Human Molecular Genetics

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show abstract

“…Recent work has suggested the psychosine inhibition of protein kinase C as a possible primary effect [10]. However, in the twitcher mouse (a model of Krabbe's disease) there is no detectable decrease in protein kinase C activity in the brain cytosol [37]. Psychosine inhibits the incorporation of galactose into myelin-associated lipids (such as cerebroside and sulphatide) in oligodendroglial, but not astrogial, cell cultures [38].…”

Section: Discussionmentioning

confidence: 99%

Kinetics of inhibition of purified and mitochondrial cytochrome c oxidase by psychosine (β-galactosylsphingosine)

Cooper

Markus

Seetulsingh

et al. 1993

Biochemical Journal

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1. Psychosine (beta-galactosylsphingosine) is the toxic agent in Krabbe's disease (globoid cells leukodystrophy). It inhibits purified bovine heart mitochondrial cytochrome c oxidase; there is a rapid phase of inhibition (complete within 10-15 s) and a slower phase (complete within 10-15 min). Both phases are also seen in rat liver mitochondria. IC50 is about 200 microM psychosine in the purified enzyme and less than 20 microM in mitochondria. Psychosine inhibition is due to binding to cytochrome oxidase, not cytochrome c. 2. Bovine heart submitochondrial particles show inhibition similar to rat liver mitochondria. However, although proteoliposomes containing bovine heart cytochrome oxidase show an identical fast phase, they have no noticeable slow phase of inhibition. Addition of phospholipid liposomes to submitochondrial particles relieved the majority of psychosine inhibition, consistent with the removal of those molecules binding in the slow phase. Psychosine can inhibit cytochrome oxidase molecules facing in either direction in proteoliposomes and submitochondrial particles, suggesting that it can rapidly interact with both sides of a membrane when added externally. 3. At high ionic strength, the presence of psychosine decreases the Vmax. of cytochrome oxidase with little effect on the Km for cytochrome c. This non-competitive inhibition suggests that the psychosine-enzyme complex is kinetically inactive and not labile over the time course of the assay. Psychosine does not inhibit the reduction of haem a or haem a3 by artificial electron donors, but does inhibit the reduction of haem a by cytochrome c.

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Protein kinase C in rat brain myelin

1992

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It has been suggested that phosphorylation of myelin basic protein (MBP) in CNS is catalyzed by protein kinase C (PKC). In order to demonstrate that PKC in the myelin phosphorylates MBP, PKC was partially purified from rat CNS myelin by solubilization with Triton X-100 followed by a DEAE-cellulose column. MBP and histone III-S were phosphorylated in the presence of Ca2+ and phospholipid by rat myelin PKC. High voltage electrophoresis revealed that the phosphoamino acids in MBP by this kinase was serine residue, which is known to be the amino acid phosphorylated by PKC. The activity of PKC extracted from myelin was inhibited by the addition of psychosine to the incubation mixture. To confirm the presence of PKC molecule and to identify the isoform of PKC in the myelin, the solubilized myelin fraction was applied on SDS-PAGE, transferred to a nitrocellulose sheet and stained with anti-PKC monoclonal antibodies. Rat CNS myelin contained the PKC of about 80 kDa (intact PKC), and no proteolytic fragments were observed. PKC isozymes in myelin were type II and III. A developmental study from 14 to 42 postnatal days showed that PKC activity in CNS myelin seemed to parallel the deposition of myelin protein.

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Accumulation of galactosylsphingosine (psychosine) does not interfere with phosphorylation and methylation of myelin basic protein in the twitcher mouse

Cited by 6 publications

References 45 publications

Missense mutation in mouse GALC mimics human gene defect and offers new insights into Krabbe disease

Missense mutation in mouse GALC mimics human gene defect and offers new insights into Krabbe disease

Kinetics of inhibition of purified and mitochondrial cytochrome c oxidase by psychosine (β-galactosylsphingosine)

Protein kinase C in rat brain myelin

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