Schwann Cell‐Specific ATG7 ‐Dependent Autophagy Protects Myelin in a Mouse Model of Krabbe Disease

Krabbe disease (KD) is a lysosomal storage disorder characterized by severe peripheral demyelination caused by mutations in galactosylceramidase (GALC), leading to the accumulation of galactosylceramide and psychosine. Although psychosine toxicity is central to KD pathology, additional mechanisms likely contribute to myelin dysfunction. Because Schwann cells (SCs) play a critical role in myelin maintenance, and GALC deficiency disrupts lysosomal function, we hypothesized that autophagy is altered in SCs during KD progression. Using a SC‐specific Galc conditional knockout ( Galc SC cKO) mouse model, we identified early changes in autophagy‐related protein levels and increased autophagosome abundance during the pre‐symptomatic phase, prior to detectable myelin abnormalities. To assess whether autophagy contributes to disease progression, we selectively deleted Atg7 , an essential regulator of canonical autophagy, in SCs. Atg7 deletion alone did not affect myelin or behavior, but its loss in Galc SC cKO mice markedly worsened disease severity. Atg7‐Galc SC cKO mice exhibited significantly thinner myelin and pronounced deficits in motor performance and nerve conduction, accompanied by altered steady‐state levels of autophagy‐associated proteins and functional decline. Notably, Atg7 deletion in Galc SC cKO mice did not further increase macrophage abundance, suggesting that the worsened myelin phenotype occurs without additional macrophage recruitment at this stage. Together, these findings demonstrate that autophagy‐associated changes occur early in KD and ATG7‐dependent pathways play a protective role during disease progression. Modulating ATG7‐dependent pathways may therefore warrant further investigation as a strategy to support myelin maintenance in KD and related lysosomal disorders.