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A Drosophila model of mucopolysaccharidosis IIIB
Bibhu Simkhada1, Nestor O Nazario-Yepiz1, Patrick S Freymuth1
1Department of Genetics and Biochemistry and Center for Human Genetics, Clemson University, 114 Gregor Mendel Circle, Greenwood, SC 29646, USA.
Abstract:
Mucopolysaccharidosis type IIIB is a rare lysosomal storage disorder caused by defects in alpha-N-acetylglucosaminidase (NAGLU) and characterized by severe effects in the central nervous system. Mutations in NAGLU cause accumulation of partially degraded heparan sulfate in lysosomes. The consequences of these mutations on whole-genome gene expression and their causal relationships to neural degeneration remain unknown. Here, we used the functional Drosophila melanogaster ortholog of NAGLU, Naglu, to develop a fly model for MPS IIIB induced by gene deletion (NagluKO), missense (NagluY160C), and nonsense (NagluW422X) mutations. We used the Drosophila activity monitoring system to analyze activity and sleep and found sex- and age-dependent hyperactivity and sleep defects in mutant flies. Fluorescence microscopy on mutant fly brains using Lysotracker dye revealed a significant increase in acidic compartments. Differentially expressed genes determined from RNA sequencing of fly brains are involved in biological processes that affect nervous system development. A genetic interaction network constructed using known interacting partners of these genes consists of 2 major subnetworks, one of which is enriched in genes associated with synaptic function and the other with neurodevelopmental processes. Our data indicate that lysosomal dysfunction arising from disruption of heparan sulfate breakdown has widespread effects on the steady state of intracellular vesicle transport, including vesicles associated with synaptic transmission. Evolutionary conservation of fundamental biological processes predicts that the Drosophila model of mucopolysaccharidosis type IIIB can serve as an in vivo system for the future development of therapies for mucopolysaccharidosis type IIIB and related disorders.
Insights
Mucopolysaccharidosis type IIIB (MPS IIIB) is a lysosomal storage disorder. A new Drosophila model reveals that NAGLU gene defects cause hyperactivity, sleep issues, and neurodevelopmental changes, offering a platform for therapy development.
Area of Science:
- Genetics
- Neuroscience
- Lysosomal Storage Disorders
Background:
- Mucopolysaccharidosis type IIIB (MPS IIIB) is a rare genetic disorder caused by alpha-N-acetylglucosaminidase (NAGLU) deficiency, leading to heparan sulfate accumulation and severe central nervous system effects.
- The impact of NAGLU mutations on gene expression and neural degeneration in MPS IIIB is not fully understood.
Purpose of the Study:
- To develop a Drosophila melanogaster model for MPS IIIB to investigate the consequences of NAGLU dysfunction.
- To analyze the effects of MPS IIIB on behavior, brain pathology, and gene expression in vivo.
Main Methods:
- Created Drosophila models of MPS IIIB using Naglu gene deletion and missense/nonsense mutations.
- Utilized Drosophila activity monitoring to assess behavior and sleep patterns.
- Employed fluorescence microscopy and RNA sequencing to examine brain pathology and gene expression profiles.
Main Results:
- Mutant flies exhibited sex- and age-dependent hyperactivity and sleep disturbances.
- Increased acidic compartments were observed in the brains of mutant flies.
- RNA sequencing identified differentially expressed genes involved in nervous system development and synaptic function.
Conclusions:
- Lysosomal dysfunction due to impaired heparan sulfate breakdown significantly impacts neural development and synaptic transmission.
- The Drosophila MPS IIIB model provides a valuable in vivo system for studying disease mechanisms and developing potential therapies.
