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other·neurology, pediatrics, biomedical research, preclinical research·PMC10474820

Galactosylceramidase deficiency and pathological abnormalities in cerebral white matter of Krabbe disease

Neurobiology of disease · 11 authors, 5 centres

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TL;DR

This study analyzed postmortem brain tissues from Krabbe disease patients and controls to examine galactosylceramidase (GALC) protein levels, enzyme activity, and neuropathology.

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Using custom antibodies, it demonstrated that GALC protein is predominantly localized to oligodendrocytes in normal infant brain white matter. The research found that homozygous null GALC mutations in infantile KD led to a deficiency in total GALC protein and activity, while a later-onset case showed normal total GALC protein levels but reduced activity. A 5-fold increase in psychosine levels was quantified in infantile KD cases. Neuropathological analysis revealed that a more severe, early-infantile case (age of death 10 months) had about a 3-fold increase in both globoid cells and CD8-positive T lymphocytes compared to a slower-progressing case (age of death 21 months), suggesting a correlation between clinical severity and neuropathology. Limitations include the small sample size and variable tissue quality from autopsy samples.

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other

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neurology

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ORIGINAL PAPER

PMC10474820

Galactosylceramidase deficiency and pathological abnormalities in cerebral white matter of Krabbe disease

Neurobiology of disease

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ABSTRACT

Krabbe Disease (KD) is an autosomal recessive disorder that results from loss-of-function mutations in the GALC gene, which encodes lysosomal enzyme galactosylceramidase (GALC). Functional deficiency of GALC is toxic to myelin-producing cells, which leads to progressive demyelination in both the central and peripheral nervous systems. It is hypothesized that accumulation of psychosine, which can only be degraded by GALC, is a primary initiator of pathologic cascades. Despite the central role of GALC in KD pathomechanism, investigations of GALC deficiency at a protein level are largely absent, due in part, to the lack of sensitive antibodies in the field. Leveraging two custom antibodies that can detect GALC at endogenous levels, we demonstrated that GALC protein is predominantly localized to oligodendrocytes in cerebral white matter of an infant brain, consistent with its functional role in myelination. Mature GALC could also be quantitatively detected as a 26 kDa band by western blotting and correlated to enzyme activity in brain tissues. The p.Ile562Thr polymorphic variant, which is over-represented in the KD population, was associated with reduced mature GALC protein and activity. In three infantile KD cases, homozygous null mutations in GALC lead to deficiency in total GALC protein and activity. Interestingly, although GALC activity was absent, normal levels of total GALC protein were detected by a sandwich ELISA using our custom antibodies in a later-onset KD brain, which suggests that the assay has the potential to differentiate infantile- and later-onset KD cases. Among the infantile KD cases, we quantified a 5-fold increase in psychosine levels, and observed increased levels of acid ceramidase, a key enzyme for psychosine production, and hyperglycosylated lysosomal-associated membrane protein 1, a marker for lysosomal activation, in periventricular white matter, a major pathological brain region, when compared with age-matched normal controls. While near complete demyelination was observed in these cases, we quantified that an early-infantile case (age of death at 10 months) had about 3-fold increases in both globoid cells, a pathological hallmark for KD, and CD8-positive T lymphocytes, a pathological marker for multiple sclerosis, in the white matter when compared with a slower progressing infantile case (age of death at 21 months), which suggests a positive correlation between clinical severity and neuropathology. Taken together, our findings have advanced the understanding of GALC protein biology in the context of normal and KD brain white matter. We also revealed new neuropathological changes that may provide insights to understand KD pathogenesis.

CITATION EXPORT

Diego Iacono, Shunsuke Koga, Hui Peng et al.. Galactosylceramidase deficiency and pathological abnormalities in cerebral white matter of Krabbe disease. Neurobiology of disease. (2022). https://doi.org/10.1016/j.nbd.2022.105862

AUTHORS

11 · 5 CENTRES

Diego Iacono, Shunsuke Koga, Hui Peng, Arulmani Manavalan, Jessica Daiker, Monica Castanedes-Casey, Nicholas B. Martin, Aimee R. Herdt, Michael H. Gelb, Dennis W. Dickson, Chris W. Lee

aBiomedical Research Institute of New Jersey (BRInj), Cedar Knolls, NJ, United States of America
bAtlantic Health System, Morristown, NJ, United States of America
cMid-Atlantic Neonatology Associates (MANA), Morristown, NJ, United States of America
dDepartment of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, United States of America
eDepartments of Chemistry and Biochemistry, University of Washington, Seattle, WA, United States of America