Disease relevance of Galc

• Detection of GALC activity and flow cytometry showed that NSPC-GALC and NSPC expressing the green fluorescent protein were attracted to the posterior area of twitcher brain, where demyelination occurs first [1].
• The expression of IL-6 is greatly enhanced in the twitcher mouse (S. M. LeVine and D. C. Brown, 1997, J. Neuroimmunol. 73, 47-56), which is an authentic animal model of globoid cell leukodystrophy (Krabbe's disease) [2].
• Globoid cell leukodystrophy (GLD) is a lysosomal storage disease caused by genetic deficiency of galactocerebrosidase (GALC) activity [3].
• Globoid cell leukodystrophy (Krabbe disease) is an autosomal recessive inherited neurodegenerative disorder caused by the deficiency of the lysosomal enzyme beta-galactosylceramidase [4].
• The effects of congenic hematopoietic cell transplantation (HCT; transplantation of bone marrow and spleen cells) after graded doses of busulfan (BU), a myeloablative but nonimmunosuppressive alkylating agent, were evaluated in the twitcher mouse model of human galactosylceramidase deficiency, a demyelinating sphingolipid storage disease [5].

High impact information on Galc

• To assess the role of aberrant Ia expression in the central nervous system (CNS), twitcher mice, which represent the murine model for GLD, were mated with Ia- transgenic mice [6].
• Compared with the Ia+ controls, Ia- twitcher mice showed a profound reduction in the severity of demyelinating lesions correlated with significantly fewer microglia/macrophages [6].
• "Twitcher' is a recently recognized mouse mutant which, on the basis of morphological and enzymatic criteria, represents a murine model for globoid-cell leukodystrophy in man [7].
• In the twitcher mouse, myelin sheaths develop normally in peripheral nerves until about the fifteenth day when the rate of myelination declines, demyelination begins and Krabbe-type inclusions are seen in macrophages and Schwann cells [7].
• Our results show that galactosylceramidase activity in twitcher sciatic nerves grafted into normal hosts is variable after 1-2 months but indistinguishable from those in the host nerves and much higher than those in intact twitcher nerves after 4.5-9 months [7].

Chemical compound and disease context of Galc

• Psychosine (galactosylsphingosine) accumulates in the brain of Krabbe disease (KD) patients as well as twitcher mice, a murine model of KD, resulting in loss of oligodendrocytes and myelin [8].
• At day 10 prior to onset of demyelination in twi/twi, the thymidine uptake by Schwann cells from sciatic nerves was similar regardless of genotype [9].
• Prostaglandin D2-mediated microglia/astrocyte interaction enhances astrogliosis and demyelination in twitcher [10].
• There was a significant increase in the level of LPC, indicating a phospholipase A2 (PLA2)-dependent pathobiology, in the brains of Krabbe disease patients and those of twitcher mice, an animal model of Krabbe disease [11].
• Twitcher mice treated with L-cycloserine had a significantly longer life span and a delayed onset of weight loss than vehicle-injected twitcher mice [12].

Biological context of Galc

• Twitcher mice with an additional complete deficiency of acid beta-galactosidase have the mildest phenotype with the longest lifespan and nearly rescued CNS pathology [13].
• On the other hand, brain psychosine level is increased in all twitcher mice, but galc(-/-), bgal(+/-) mice show a significantly higher level than other genotypes [13].
• These lines of evidence suggest that L-PGDS is an anti-apoptotic molecule protecting neurons and OLs from apoptosis in the twitcher mouse [14].
• Decreased fatty acylation of myelin proteolipid protein in the twitcher mouse [15].
• When the methylation of an arginine residue of MBP was examined in slices of the brainstem and spinal cord, using [3H]methionine as a donor of the methyl groups, no difference was found between Twi and the controls [16].

Anatomical context of Galc

• GALC(twi/twi) microglia, also more abundant in posterior regions of the brain, released significant amounts of the cytotoxic cytokine TNF-alpha when matched with NSPC-GALC [1].
• To verify the therapeutic potential on twitcher of neural stem/progenitor cells (NSPC), we transduced them with a GALC lentiviral vector [1].
• Dysfunction of peroxisomes in twitcher mice brain: a possible mechanism of psychosine-induced disease [8].
• Twitcher is characterized by extensive central and peripheral demyelination and the presence of intracellular inclusions in macrophages similar to human globoid cell leukodystrophy [17].
• Decreased fatty acylation of PLP was also observed in the twitcher mouse at postnatal day 20 when the isolated myelin was incubated with [14C]palmitoyl-CoA in the absence of ATP and CoA, or the slices of brainstem and spinal cord were incubated with [3H]palmitic acid [15].

Associations of Galc with chemical compounds

• IL-6 deficiency causes enhanced pathology in Twitcher (globoid cell leukodystrophy) mice [2].
• Radioactivity of the [3H] methionine residue of MBP of Twi was also similar to that of the controls [16].
• Although the absolute amount of galactosylceramide in the liver and lung was much smaller, it was also increased greatly in the twitcher mouse [18].
• Hematopoietic cell transplantation in the twitcher mouse. The effects of pretransplant conditioning with graded doses of busulfan [5].
• Suppressed UDP-galactose: ceramide galactosyltransferase and myelin protein mRNA in twitcher mouse brain [19].

Physical interactions of Galc

• Expression of major histocompatibility complex class I antigens in the demyelinating twitcher CNS and PNS [20].

Regulatory relationships of Galc

• L-PGDS is expressed in oligodendrocytes (OLs) in the central nervous system and is up-regulated in OLs of the twitcher mouse, a model of globoid cell leukodystrophy (Krabbe's disease) [21].
• In both the Twitcher and the control groups the galactosyltransferase activity rapidly increased up to 20-25 DIV and then declined [22].

Other interactions of Galc

• These observations are contrary to the expected outcome of Mendelian autosomal recessive single gene disorders and may also be interpreted as that the acid beta-galactosidase gene functions as a modifier gene for the phenotypic expression of genetic galactosylceramidase deficiency [13].
• LPS was found to greatly shorten the life of twitcher and twitcher/IL-6-deficient mice compared to genotyped-matched saline-injected mice [2].
• The possibility of the treatment of globoid cell leucodystrophy in the twitcher mouse by enzyme replacement was investigated using nerve grafts from affected animals into trembler hosts [23].
• In twitcher chimeric mice examined after 100 postnatal days, the majority of GFP/Mac-1 double-positive cells displayed the morphological features of ramified microglia with fine delicate processes and was distributed diffusely in both gray and white matter [24].
• The expression of the major histocompatibility complex class II antigens (Ia) was investigated in the central and peripheral nervous systems of the twitcher mouse, an authentic murine model of globoid cell leukodystrophy (Krabbe disease) in humans [25].

Analytical, diagnostic and therapeutic context of Galc

• This longitudinal study demonstrated that AAV2/5-GALC-mediated gene therapy resulted in higher levels of Galc expression and slowed the neurologic deterioration more completely than AAV2-GALC in the murine model of globoid-cell leukodystrophy [26].
• Prolonged survival and remyelination after hematopoietic cell transplantation in the twitcher mouse [27].
• We report that, upon transplantation, GALC-deficient OLs from the twitcher mouse, a model of GLD, achieved widespread myelination in the brain and spinal cord of the myelin-deficient shiverer mouse, which was preserved for the life of the host [3].
• GALC immunohistochemistry showed direct evidence for GALC transfer from the shiverer environment to the engrafted mutant OLs in vivo [3].
• The twitcher mouse: a model for Krabbe disease and for experimental therapies [28].

References