In a genetic mouse model of Krabbe disease, combined loss of Galc and Atg7 in Schwann cells was associated with thinner peripheral myelin and poorer nerve performance by postnatal day 60. Mice with Schwann-cell Atg7 loss alone showed no change in sciatic-nerve myelination at postnatal days 14 or 60 and did not differ from wild-type mice on the rotarod test at days 35 or 60.
The researchers were testing whether autophagy, a cellular recycling process, changes in Schwann cells alongside peripheral myelin dysfunction during GALC-deficient disease. They generated mice in which Galc was deleted only in Schwann cells and crossed them with mice carrying Schwann-cell-specific Atg7 deletion, producing a double-knockout group.
Early changes appeared before the clearest myelin loss
Peripheral pathology was reported to begin after P14, between P14 and P21, with several myelin abnormalities increased at P28.
Biochemical measurements also shifted with age. At P21, ATG7 and the LC3-II/LC3-I ratio were higher in Galc-deficient nerves, while LC3-I normalized to GAPDH was lower. Those differences were not present at P14, and LC3-II itself did not reach statistical significance.
A fluorescent LC3 reporter showed an early signal as well: the proportion of Galc-deficient Schwann cells containing yellow puncta, or small fluorescent spots, was higher as early as P7 and increased with age. But the signal did not reveal what was happening to the whole process. More puncta could reflect increased formation, impaired clearance or defective fusion with lysosomes, so the experiments did not determine autophagic flux, the rate of material moving through the pathway.
Data collection and analysis were blinded. For morphometric work, animals were treated as the biological replicates, while axons, fields or structures were subsamples; the investigators used t tests and one- or two-way ANOVA and set statistical significance at p < 0.05. The P35 reporter cohort included four animals in each of the wild-type, Galc-only and double-knockout groups, and three in the Atg7-only group.
The disease phenotype became clearer at day 60
By P60, the study's G-ratio measure of sciatic-nerve myelin thickness was 0.669 plus or minus 0.006 in wild-type mice, 0.752 plus or minus 0.001 in Galc-only mice and 0.789 plus or minus 0.008 in double-knockout mice. The reported rise from wild type to Galc-only mice, followed by a further rise after Atg7 loss, matched the pattern of progressively thinner myelin.
The morphology comparison used three animals per genotype, with individual axons treated as subsamples rather than independent animals.
At the same age, combined Galc and Atg7 loss changed the steady-state mix of autophagy-associated proteins. Compared with Galc-only nerves, the double-knockout nerves had more LC3-I, less LC3-II and a lower LC3-II/LC3-I ratio. p62 and LAMP1 were also higher, but those comparisons were not statistically significant, with p values of 0.0632 and 0.5604, respectively.
At P35, the double-knockout group also had a higher share of yellow LC3 puncta relative to total red puncta. Total red puncta and red-only puncta did not differ significantly, and the identity of the yellow structures remained unresolved, particularly in Atg7-deficient Schwann cells.
The functional differences were selective
The functional pattern was selective. Atg7-only mice did not differ from wild-type mice on the rotarod at P35 or P60, whereas double-knockout mice performed worse than Galc-only mice at P60. The double-knockout group also had lower nerve conduction velocity and increased proximal latency.
Not every measure worsened in parallel. At P60, macrophage abundance and the proportion of morphologically abnormal axons were similar in the two mutant groups. Both had lower axon density than wild type, but the double-knockout group did not have an additional reduction. The study did not fully assess macrophage activation, phagocytosis, inflammatory function or other axonal injury measures.
A signal from a mouse model, not a treatment result
The results point to an association between Schwann-cell Atg7 loss and a more severe myelin and nerve-function phenotype in this Galc-deficient mouse model. They do not show that the reporter puncta were canonical autophagosomes or that changing ATG7-dependent pathways would treat Krabbe disease. The findings come from a peripheral Schwann-cell mouse model and do not establish a treatment for people with the disease.
Animal protocols were approved by the University at Buffalo State University of New York IACUC. The work was supported by NIH grants R01NS111715, R01NS112327 and F31NS124106, along with the Rosenau Family Research Foundation. The authors reported no conflicts of interest.
Paper data and sources
Original title: Schwann Cell‐Specific ATG7‐Dependent Autophagy Protects Myelin in a Mouse Model of Krabbe Disease
Authors: Dhimal N, Sidharth A, Zhang J et al.
Journal/Repository: Glia
Status: Peer-reviewed
First online: 2026-10-11
DOI: Not available
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