Brainstem development requires galactosylceramidase and is critical for pathogenesis in a model of Krabbe disease

Nadav I. Weinstock, Conlan Kreher, Jacob Favret, Duc Nguyen, Ernesto R. Bongarzone, Lawrence Wrabetz, M. Laura Feltri and Daesung Shin ()
Additional contact information
Nadav I. Weinstock: Jacobs School of Medicine and Biomedical Sciences, University at Buffalo (SUNY)
Conlan Kreher: Jacobs School of Medicine and Biomedical Sciences, University at Buffalo (SUNY)
Jacob Favret: Jacobs School of Medicine and Biomedical Sciences, University at Buffalo (SUNY)
Duc Nguyen: College of Medicine, University of Illinois at Chicago
Ernesto R. Bongarzone: College of Medicine, University of Illinois at Chicago
Lawrence Wrabetz: Jacobs School of Medicine and Biomedical Sciences, University at Buffalo (SUNY)
M. Laura Feltri: Jacobs School of Medicine and Biomedical Sciences, University at Buffalo (SUNY)
Daesung Shin: Jacobs School of Medicine and Biomedical Sciences, University at Buffalo (SUNY)

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Krabbe disease (KD) is caused by a deficiency of galactosylceramidase (GALC), which induces demyelination and neurodegeneration due to accumulation of cytotoxic psychosine. Hematopoietic stem cell transplantation (HSCT) improves clinical outcomes in KD patients only if delivered pre-symptomatically. Here, we hypothesize that the restricted temporal efficacy of HSCT reflects a requirement for GALC in early brain development. Using a novel Galc floxed allele, we induce ubiquitous GALC ablation (Galc-iKO) at various postnatal timepoints and identify a critical period of vulnerability to GALC ablation between P4-6 in mice. Early Galc-iKO induction causes a worse KD phenotype, higher psychosine levels in the rodent brainstem and spinal cord, and a significantly shorter life-span of the mice. Intriguingly, GALC expression peaks during this critical developmental period in mice. Further analysis of this mouse model reveals a cell autonomous role for GALC in the development and maturation of immature T-box-brain-1 positive brainstem neurons. These data identify a perinatal developmental period, in which neuronal GALC expression influences brainstem development that is critical for KD pathogenesis.

Date: 2020
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-020-19179-w Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19179-w

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-020-19179-w

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().