These data lead us to hypothesize on putative mechanisms linked to PARP-1 signaling that are aberrant in three exemplar leukodystrophy diseases associated with demyelination: Krabbe disease, X-linked adrenoleukodystrophy, and Metachromatic leukodystrophy, for which no therapeutic options currently exist. Here, PARP1 is linked to metachromatic leukodystrophy.