Understanding the Role of Autophagy in Neurodegeneration Associated with Mucopolysaccharidosis Type VII and Exploring Novel Therapeutic Targets

Das, Apurba (2025) Understanding the Role of Autophagy in Neurodegeneration Associated with Mucopolysaccharidosis Type VII and Exploring Novel Therapeutic Targets. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Apurba Das (18RS035)) 18RS035.pdf - Submitted Version Restricted to Repository staff only Download (4MB)

Abstract

Mucopolysaccharidosis type VII is a lysosomal storage disease caused by a deficiency of β-glucuronidase. The absence of β-glucuronidase leads to an increase in undegraded glycosaminoglycans, affecting multiple organs and causing premature death in most cases. The FDA-approved enzyme replacement therapy is very expensive and fails to ameliorate the neurodegenerative symptoms of the disease, thereby highlighting the need for a better understanding of the mechanism of neurodegeneration and the exploration of alternative therapies. Utilising the Drosophila model of MPS VII, we investigated the mechanism of neurodegeneration. Previously reported, the MPS VII fly brain had increased ubiquitinated proteins and mitochondria, along with engorged lysosomes in the brain, suggesting a defect in cellular clearance. To find the underlying reason, we hypothesised the involvement of the autophagy pathway. Our preliminary findings revealed that the MPS VII flies were much more susceptible to starvation, suggesting an autophagy defect in MPS VII. Taking cues from this observation, we assessed the autophagy pathway in their brain to dissect the underlying cause of neurodegeneration. We found significant reductions in expression of autophagy-related genes Atg8a, Ref(2)P, and Atg1 levels, indicating autophagy impairment in the MPS VII brain. The investigation of autophagy regulatory factors implicated downregulation of Mitf and alteration in mTOR activity as the underlying reason for the autophagy defect. Further investigation of the MPS VII fly brain found the presence of elevated lipofuscin and multilamellar bodies, indicating a decrease in lysosomal activity. We identified the Mitf-vATPase-mTOR axis as a therapeutic target. Autophagy activation using resveratrol and trehalose showed promising restoration of neurological defects in the MPS VII fly brain. Correction of the autophagy defect decreased apoptotic death in the MPS VII brain. Our work unravelled the mechanism of neurodegeneration and identified pharmacologically targetable molecules to alleviate neuropathology in MPS VII.

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