Brainstem development requires galactosylceramidase and is critical for pathogenesis in a model of Krabbe disease.
Nadav I WeinstockConlan KreherJacob FavretDuc NguyenErnesto R BongarzoneLawrence WrabetzMaria Laura FeltriDaesung ShinPublished in: Nature communications (2020)
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.
Keyphrases
- spinal cord
- mouse model
- poor prognosis
- end stage renal disease
- preterm infants
- white matter
- transcription factor
- newly diagnosed
- binding protein
- radiofrequency ablation
- metabolic syndrome
- machine learning
- pregnant women
- spinal cord injury
- stem cells
- type diabetes
- prognostic factors
- acute myeloid leukemia
- cerebral ischemia
- climate change
- skeletal muscle
- bone marrow
- brain injury
- big data
- blood brain barrier
- artificial intelligence
- cell therapy
- patient reported outcomes
- electronic health record
- functional connectivity
- atrial fibrillation
- smoking cessation
- replacement therapy
- hematopoietic stem cell