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


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.

SUBMITTER: Weinstock NI 

PROVIDER: S-EPMC7584660 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Weinstock Nadav I NI   Kreher Conlan C   Favret Jacob J   Nguyen Duc D   Bongarzone Ernesto R ER   Wrabetz Lawrence L   Feltri M Laura ML   Shin Daesung D  

Nature communications 20201023 1


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 (Ga  ...[more]

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