2025-11-11 | Trehalose-mediated activation of Mitf corrects autophagy defects and ameliorates neurodegeneration in MPS VII
Abstract 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.
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2025-07-04 | CRISPR/Cas9-mediated promoterless gene targeting reduces lysosome storage in MPS VII mice.
Targeted gene integration mediated by CRISPR/Cas9 is a promising therapeutic strategy for monogenic autosomal recessive diseases. In this study, we established a novel all-in-one high-capacity adenovirus (HCAd) that can pack both CRISPR/Cas9 and donor DNA into the same vector and tested it on a mouse model of mucopolysaccharidosis type VII (MPS VII) caused by mutations in the β-glucuronidase (GUSB) gene. This system allowed targeted integration of promoterless GUSB in the mouse beta-actin gene (mActb) locus and the co-expression of GUSB with the self-cleaving peptide T2A (T2A) controlled by a strong endogenous mActb promoter. The in vivo results indicated that the serum GUSB level of MPS VII mice treated with a single intraperitoneal injection of the HCAd vector achieved 14% of that of wild-type mice, resulting in significant amelioration of lysosomal storage in the liver and spleen. Furthermore, the HCAd was injected intraventricularly in the brain of newborn MPS VII mice, leading to strongly positive GUSB enzyme staining in the choroid plexus and perivascular spaces of the periventricular regions and reduced lysosome storage. In summary, by using an all-in-one vector, the study provides a universal, one-for-all therapeutic for MPSVII, a disease caused by different mutations of the GUSB gene.
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2025-02-06 | Unravelling a mechanistic link between mitophagy defect, mitochondrial malfunction, and apoptotic neurodegeneration in Mucopolysaccharidosis VII.
Cognitive disability and neurodegeneration are prominent symptoms of Mucopolysaccharidosis VII (MPS VII), a lysosomal storage disorder caused by β-glucuronidase enzyme deficiency. Yet, the mechanism of neurodegeneration in MPS VII remains unclear thereby limiting the scope of targeted therapy. We aimed to bridge this knowledge gap by employing the β-glucuronidase-deficient (CG2135-/-) Drosophila model of MPS VII. Taking cues from our initial observation that the adult CG2135-/- flies displayed enhanced susceptibility to starvation, we investigated potential impairments in the autophagy-lysosomal clearance machinery in their brain to dissect the underlying cause of neurodegeneration. We found that both autophagosome biogenesis and lysosome-mediated autophagosomal turnover were impaired in the CG2135-/- fly brain. This was evidenced by lower Atg8a-II levels, reduced Atg1 and Ref(2)P expression along with accumulation of lipofuscin-like inclusions and multilamellar bodies. Mitophagy was also found to be defective in their brain, resulting in buildup of enlarged mitochondria with distorted cristae and reduced membrane potential. This, in turn, compromised mitochondrial function, as reflected by drastically reduced brain ATP levels. Energy depletion triggered apoptosis in neuronal as well as non-neuronal cells of the CG2135-/- fly brain, where apoptotic dopaminergic neurons were also detected. Interestingly, resveratrol treatment corrected the mitophagy defect and prevented ATP depletion in the CG2135-/- fly brain, providing an explanation for its neuroprotective effects. Collectively, our study reveals a pharmacologically targetable mechanistic link between mitophagy defect, mitochondrial malfunction, and apoptotic neurodegeneration in MPS VII.
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