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.

Mechanisms of demyelination and neurodegeneration in globoid cell leukodystrophy

“…Fusion GALC in these mice is tethered to the lysosomal membrane protein LAMP1. The second group followed a more traditional approach and engineered a GALC floxed allele allowing endogenous GALC expression, secretion, and thus cross‐correction (Weinstock, Kreher, et al, 2020; Weinstock, Shin, et al, 2020) In both studies, Galc floxed animals were crossed to Mpz‐Cre , which express Cre specifically in Schwann cells. The data generated from both studies showed definitively that Schwann cells produce psychosine autonomously, which is sufficient to generate a severe demyelinating neuropathy.…”

Dystonia-specific mutations in THAP1 alter transcription of genes associated with neurodevelopment and myelin

“…We identified dysregulation of myelin-related transcripts associated with THAP1/Thap1 disruption, including consistent downregulation of galactosylceramidase ( GALC ), which encodes a lysosomal enzyme that catabolizes the major lipid constituents of myelin. Mutations in the gene cause an autosomal recessive neurodevelopmental disorder with leukoencephalopathy and demyelination, 79 and enzyme deficiency in mice results in reduced proliferative potential in NSCs and functional impairment of neuronal and oligodendroglial progeny. 80 Further, we identified modules of genes that were correlated with THAP1 perturbation and functionally associated with YY1 targets, lipid metabolism, and myelination.…”

Lysosomal Functions in Glia Associated with Neurodegeneration

“…Abnormalities in myelination are often encountered in lysosomal storage diseases (LSDs) such as globoid cell leukodystrophy or Krabbe disease (KD), which is characterized primarily by the loss of myelin and accumulation of a cytotoxic metabolite, psychosine [ 55 , 56 ]. mTOR-independent autophagy enhancers, such as lithium, have been demonstrated to activate autophagy and improve cell viability post-psychosine exposure in an in vitro model of oligodendrocytes [ 57 ].…”