Heterozygote galactocerebrosidase (GALC) mutants have reduced remyelination and impaired myelin debris clearance following demyelinating injury

Abstract

Genome-wide association studies are identifying multiple genetic risk factors for several diseases, but the functional role of these changes remains mostly unknown. Variants in the galactocerebrosidase (GALC) gene, for example, were identified as a risk factor forMultiple Sclerosis (MS); however, the potential biological relevance of GALC variants toMS remains elusive. We found that heterozygote GALC mutant mice have reducedmyelin debris clearance and diminished remyelination after a demyelinating insult. We found no histological or behavioral differences between adult wild-type and GALC+/- animals under normal conditions. Following exposure to the demyelinating agent cuprizone, however, GALC+/- animals had significantly reduced remyelination during recovery. In addition, themicroglial phagocytic response and elevation of Trem2, both necessary for clearing damagedmyelin, were markedly reduced in GALC+/- animals. These altered responses could be corrected in vitro by treatment with NKH-477, a compound discovered as protective in our previous studies on Krabbe disease, which is caused bymutations in both GALC alleles. Our data are the first to show remyelination defects in individuals with a singlemutant GALC allele, suggesting such carriersmay have increased vulnerability tomyelin damage following injury or disease due to inefficientmyelin debris clearance.We thus provide a potential functional link between GALC variants and increased MS susceptibility, particularly due to the failure of remyelination associated with progressive MS. Finally, this work demonstrates that genetic variants identified through genome-wide association studiesmay contribute significantly to complex diseases, not by driving initial symptoms, but by altering repair mechanisms.