Lipid metabolic perturbation is an early-onset phenotype in adult spinster mutants: a Drosophila model for lysosomal storage disorders.
Lipid metabolic perturbation is an early-onset phenotype in adult spinster mutants: a Drosophila model for lysosomal storage disorders.
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DOI：
10.1091/mbc.e16-09-0674
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发表时间：
2017-12-15
影响因子：
3.3
通讯作者：
Schwudke D
中科院分区：
文献类型：
--
作者：
Hebbar S;Khandelwal A;Jayashree R;Hindle SJ;Chiang YN;Yew JY;Sweeney ST;Schwudke D
脑鞘脂代谢扰动的动力学的背景下，神经变性的进展中的spinster突变体，果蝇模型的溶酶体贮积症。此外，在本研究中描述的自旋与脂质载体蛋白Lipophorin的相互作用突出了脂质代谢扰动的多器官性质。脂质的细胞内积累和肿胀的功能障碍性溶酶体与几种神经退行性疾病有关，包括溶酶体贮积症（LSD）。脂质代谢变化与神经退行性变的发生和进展的详细特征目前尚不清楚。我们系统地分析了脂质扰动的spinster（自旋）突变体，果蝇模型的LSD样神经变性。我们的研究结果强调了在神经退行性变的早期阶段，脑神经酰胺和鞘氨醇的不平衡，在内膜结构的积累，行为改变的表现和脂褐素的积累之前。操纵神经酰胺酶水平和改变自旋突变体中的这些脂质使我们能够得出结论，神经酰胺稳态是疾病进展的驱动力，并且是成人神经系统中自旋功能不可或缺的。我们确定了29种新的自旋物理相互作用伙伴，并专注于脂质载体蛋白，脂蛋白（LPP）。Lpp和Spin的一个子集共定位于大脑和专门用于脂质代谢的器官（脂肪体和卵母细胞）内。在自旋突变体组织中观察到Lpp蛋白减少。最后，增加水平的脂质代谢物产生的卵母细胞在自旋突变体暗示自旋和LPP之间的功能相互作用，强调了LSD的脂质扰动的系统性。
The kinetics of brain sphingolipid metabolic perturbation were determined in the context of progression of neurodegeneration in spinster mutants, a Drosophila model of lysosomal storage disorders. Further, an interaction of Spin with the lipid carrier protein Lipophorin described in this study highlights the multi-organ nature of the lipid metabolic perturbation. 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.