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Hebbar, S., Khandelwal, A., Jayashree, R., Hindle, S.J., Chiang, Y.N., Yew, J.Y., Sweeney, S.T., Schwudke, D. (2017). Lipid metabolic perturbation is an early-onset phenotype in adult spinster mutants: a Drosophila model for lysosomal storage disorders.  Mol. Biol. Cell 28(26): 3728--3740.
FlyBase ID
FBrf0237598
Publication Type
Research paper
Abstract

Intracellular accumulation of lipids and swollen dysfunctional lysosomes are linked to several neurodegenerative diseases, including lysosomal storage disorders (LSD). Detailed characterization of lipid metabolic changes in relation to the onset and progression of neurodegeneration is currently missing. We systematically analyzed lipid perturbations in spinster (spin) mutants, a Drosophila model of LSD-like neurodegeneration. Our results highlight an imbalance in brain ceramide and sphingosine in the early stages of neurodegeneration, preceding the accumulation of endomembranous structures, manifestation of altered behavior, and buildup of lipofuscin. Manipulating levels of ceramidase and altering these lipids in spin mutants allowed us to conclude that ceramide homeostasis is the driving force in disease progression and is integral to spin function in the adult nervous system. We identified 29 novel physical interaction partners of Spin and focused on the lipid carrier protein, Lipophorin (Lpp). A subset of Lpp and Spin colocalize in the brain and within organs specialized for lipid metabolism (fat bodies and oenocytes). Reduced Lpp protein was observed in spin mutant tissues. Finally, increased levels of lipid metabolites produced by oenocytes in spin mutants allude to a functional interaction between Spin and Lpp, underscoring the systemic nature of lipid perturbation in LSD.

PubMed ID
PubMed Central ID
PMC5739291 (PMC) (EuropePMC)
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    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Mol. Biol. Cell
    Title
    Molecular Biology of the Cell
    Publication Year
    1992-
    ISBN/ISSN
    1059-1524
    Data From Reference
    Alleles (7)
    Gene Groups (1)
    Genes (4)
    Human Disease Models (1)
    Transgenic Constructs (3)