Trehalose-mediated activation of Mitf corrects autophagy defects and ameliorates neurodegeneration in MPS VII

Mucopolysaccharidosis type VII (MPS VII) is a progressive lysosomal storage disorder caused by β-glucuronidase (β-GUS) deficiency, featuring pronounced neurodegeneration. The Drosophila model of MPS VII, generated by deleting the fly β-GUS ortholog CG2135, exhibits hallmark neuropathological features, including dopaminergic neuron loss, brain vacuolisation, and impaired locomotor performance. Using this CG2135 ^−/− fly, we recently showed that impaired autophagosome formation and their turnover led to abnormal accumulation of damaged mitochondria and lipofuscins in the brain. In this study, we investigated the molecular basis of this autophagy defect and found that Mitf (the TFEB homolog), the transcriptional regulator of autophagy, is markedly downregulated in CG2135 ^−/− fly brains, accompanied by reduced expression of its target genes, including LAMP1, CLN3, and v-ATPase subunits. Guided by these observations, we assessed whether boosting Mitf activity could ameliorate neuropathology. Interestingly, oral trehalose treatment reactivated Mitf and its downstream autophagy gene network in CG2135 ^−/− fly brains, restoring autophagosome biogenesis, reducing lipofuscin accumulation, and alleviating apoptosis. Trehalose treatment also improved locomotor performance, indicating a clear mitigation of neurodegeneration. These findings demonstrate that Mitf dysregulation drives autophagy impairment in MPS VII fly brain and highlight Mitf activation as a promising therapeutic strategy to alleviate neurological pathology.