Altered Trafficking and Processing of GALC Mutants Correlates with Globoid Cell Leukodystrophy Severity

Overview

Journal J Neurosci

Specialty Neurology

Date 2016 Feb 12

PMID 26865610

Citations 22

Authors

Daesung Shin

M Laura Feltri

Lawrence Wrabetz

Affiliations

Soon will be listed here.

Abstract

Significance Statement: Globoid cell leukodystrophy (GLD, Krabbe disease) is diagnosed by measuring galactosylceramidase (GALC) activity and DNA analysis. However, genotype and phenotype often do not correlate due to considerable clinical variability, even for the same mutation, for unknown reasons. We find that altered trafficking to the lysosome and processing of GALC correlates with GLD severity and is modulated by cis-polymorphisms. Current diagnosis of GLD is based on GALC activity of total cell lysates from blood, which does not discriminate whether the activity comes from the lysosome or other subcellular organelles. Measurement of GALC activity in lysosomes may predict which infants are at high risk for the infantile phenotype while distinguishing other children who will develop later-onset phenotypes without onset of symptoms for years.

Citing Articles

Human iPSC-derived myelinating organoids and globoid cells to study Krabbe disease.

Evans L, Gawron J, Sim F, Feltri M, Marziali L PLoS One. 2024; 19(12):e0314858.

PMID: 39636943 PMC: 11620608. DOI: 10.1371/journal.pone.0314858.

Human iPSC-derived myelinating organoids and globoid cells to study Krabbe Disease.

Evans L, Gawron J, Sim F, Feltri M, Marziali L bioRxiv. 2024; .

PMID: 39091729 PMC: 11291050. DOI: 10.1101/2024.07.19.604372.

Late-onset Krabbe disease presenting as spastic paraplegia - implications of GCase and CTSB/D.

Machtel R, Dobert J, Hehr U, Weiss A, Kettwig M, Laugwitz L Ann Clin Transl Neurol. 2024; 11(7):1715-1731.

PMID: 38837642 PMC: 11251474. DOI: 10.1002/acn3.52078.

Perinatal loss of galactosylceramidase in both oligodendrocytes and microglia is crucial for the pathogenesis of Krabbe disease in mice.

Favret J, Nawaz M, Patel M, Khaledi H, Gelb M, Shin D Mol Ther. 2024; 32(7):2207-2222.

PMID: 38734898 PMC: 11286809. DOI: 10.1016/j.ymthe.2024.05.019.

Claudin-11 in health and disease: implications for myelin disorders, hearing, and fertility.

Gjervan S, Ozgoren O, Gow A, Stockler-Ipsiroglu S, Pouladi M Front Cell Neurosci. 2024; 17:1344090.

PMID: 38298375 PMC: 10827939. DOI: 10.3389/fncel.2023.1344090.

References

Ribbens J, Whiteley G, Furuya H, Southall N, Hu X, Marugan J . A high-throughput screening assay using Krabbe disease patient cells. Anal Biochem. 2012; 434(1):15-25. PMC: 3975245. DOI: 10.1016/j.ab.2012.10.034. View

Shin D, Howng S, Ptacek L, Fu Y . miR-32 and its target SLC45A3 regulate the lipid metabolism of oligodendrocytes and myelin. Neuroscience. 2012; 213:29-37. PMC: 3370422. DOI: 10.1016/j.neuroscience.2012.03.054. View

Hossain M, Otomo T, Saito S, Ohno K, Sakuraba H, Hamada Y . Late-onset Krabbe disease is predominant in Japan and its mutant precursor protein undergoes more effective processing than the infantile-onset form. Gene. 2013; 534(2):144-54. DOI: 10.1016/j.gene.2013.11.003. View

DAntonio M, Musner N, Scapin C, Ungaro D, Del Carro U, Ron D . Resetting translational homeostasis restores myelination in Charcot-Marie-Tooth disease type 1B mice. J Exp Med. 2013; 210(4):821-38. PMC: 3620355. DOI: 10.1084/jem.20122005. View

Rubenstein R, Zeitlin P . Sodium 4-phenylbutyrate downregulates Hsc70: implications for intracellular trafficking of DeltaF508-CFTR. Am J Physiol Cell Physiol. 2000; 278(2):C259-67. DOI: 10.1152/ajpcell.2000.278.2.C259. View

Harzer K, Knoblich R, Rolfs A, Bauer P, Eggers J . Residual galactosylsphingosine (psychosine) beta-galactosidase activities and associated GALC mutations in late and very late onset Krabbe disease. Clin Chim Acta. 2002; 317(1-2):77-84. DOI: 10.1016/s0009-8981(01)00791-4. View

Yagi T, Matsuda J, Takikita S, Mohri I, Suzuki K, Suzuki K . Comparative clinico-pathological study of saposin-A-deficient (SAP-A-/-) and Twitcher mice. J Neuropathol Exp Neurol. 2004; 63(7):721-34. DOI: 10.1093/jnen/63.7.721. View

Feltri M, Scherer S, Wrabetz L, Kamholz J, Shy M . Mitogen-expanded Schwann cells retain the capacity to myelinate regenerating axons after transplantation into rat sciatic nerve. Proc Natl Acad Sci U S A. 1992; 89(18):8827-31. PMC: 50014. DOI: 10.1073/pnas.89.18.8827. View

Chen Y, Rafi M, de Gala G, Wenger D . Cloning and expression of cDNA encoding human galactocerebrosidase, the enzyme deficient in globoid cell leukodystrophy. Hum Mol Genet. 1993; 2(11):1841-5. DOI: 10.1093/hmg/2.11.1841. View

10.

Jung M, Kramer E, Grzenkowski M, Tang K, Blakemore W, Aguzzi A . Lines of murine oligodendroglial precursor cells immortalized by an activated neu tyrosine kinase show distinct degrees of interaction with axons in vitro and in vivo. Eur J Neurosci. 1995; 7(6):1245-65. DOI: 10.1111/j.1460-9568.1995.tb01115.x. View

11.

Rafi M, Luzi P, Zlotogora J, Wenger D . Two different mutations are responsible for Krabbe disease in the Druze and Moslem Arab populations in Israel. Hum Genet. 1996; 97(3):304-8. DOI: 10.1007/BF02185759. View

12.

Luzi P, Rafi M, Wenger D . Multiple mutations in the GALC gene in a patient with adult-onset Krabbe disease. Ann Neurol. 1996; 40(1):116-9. DOI: 10.1002/ana.410400119. View

13.

Maestri N, Brusilow S, Clissold D, Bassett S . Long-term treatment of girls with ornithine transcarbamylase deficiency. N Engl J Med. 1996; 335(12):855-9. DOI: 10.1056/NEJM199609193351204. View

14.

De Gasperi R, Gama Sosa M, Sartorato E, Battistini S, Macfarlane H, Gusella J . Molecular heterogeneity of late-onset forms of globoid-cell leukodystrophy. Am J Hum Genet. 1996; 59(6):1233-42. PMC: 1914878. View

15.

Chen W, Bailey E, McCune S, Dong J, Townes T . Reactivation of silenced, virally transduced genes by inhibitors of histone deacetylase. Proc Natl Acad Sci U S A. 1997; 94(11):5798-803. PMC: 20860. DOI: 10.1073/pnas.94.11.5798. View

16.

Furuya H, Kukita Y, Nagano S, Sakai Y, Yamashita Y, Fukuyama H . Adult onset globoid cell leukodystrophy (Krabbe disease): analysis of galactosylceramidase cDNA from four Japanese patients. Hum Genet. 1997; 100(3-4):450-6. DOI: 10.1007/s004390050532. View

17.

Satoh J, TOKUMOTO H, Kurohara K, Yukitake M, Matsui M, Kuroda Y . Adult-onset Krabbe disease with homozygous T1853C mutation in the galactocerebrosidase gene. Unusual MRI findings of corticospinal tract demyelination. Neurology. 1997; 49(5):1392-9. DOI: 10.1212/wnl.49.5.1392. View

18.

Nagano S, Yamada T, Shinnoh N, Furuya H, Taniwaki T, Kira J . Expression and processing of recombinant human galactosylceramidase. Clin Chim Acta. 1998; 276(1):53-61. DOI: 10.1016/s0009-8981(98)00095-3. View

19.

Raghavan S, Zeng B, Torres P, Pastores G, Kolodny E, Kurtzberg J . Globoid cell leukodystrophy (Krabbe disease): normal umbilical cord blood galactocerebrosidase activity and polymorphic mutations. J Inherit Metab Dis. 2006; 28(6):1005-9. DOI: 10.1007/s10545-005-4138-z. View

20.

Xu C, Sakai N, Taniike M, Inui K, Ozono K . Six novel mutations detected in the GALC gene in 17 Japanese patients with Krabbe disease, and new genotype-phenotype correlation. J Hum Genet. 2006; 51(6):548-554. DOI: 10.1007/s10038-006-0396-3. View