Glial Lipid Droplets and ROS Induced by Mitochondrial Defects Promote Neurodegeneration
By Lucy Liu, Ke Zhang, Héctor Sandoval, Shinya Yamamoto, Manish Jaiswal, E. Sanz, Zhihong Li, Jessica C M Hui, B. Graham, Albert Quintana and 1 more. Cell, 2015
805 citations recorded by the source corpus.
Reactive oxygen species (ROS) and mitochondrial defects in neurons are implicated in neurodegenerative disease. Here we find that a key consequence of ROS and neuronal mitochondrial dysfunction is the accumulation of lipid droplets (LD) in glia. In Drosophila, ROS triggers c-Jun-N-terminal Kinase (JNK) and Sterol Regulatory Element Binding Protein (SREBP) activity in neurons leading to LD accumulation in glia prior to or at the onset of neurodegeneration. The accumulated lipids are peroxidated in the presence of ROS. Reducing LD accumulation in glia and lipid peroxidation via targeted lipase overexpression and/or lowering ROS significantly delays the onset of neurodegeneration. Furthermore, a similar pathway leads to glial LD accumulation in Ndufs4 mutant mice with neuronal mitochondrial defects, suggesting that LD accumulation following mitochondrial dysfunction is an evolutionarily conserved phenomenon, and represents an early, transient indicator and promoter of neurodegenerative disease.
Subfields: Biochemistry, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/96a85eee6a3464858029dcc492d6c9344337bf00
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Citations in the corpus
- ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020, background): “Antioxidant treatment or human superoxide dismutase 1 (SOD1) expression in flies reduces LD formation and attenuates neurodegeneration [163].”
- Antioxidant Role for Lipid Droplets in a Stem Cell Niche of Drosophila (2015, positive): “This study reveals an antioxidant role for lipid droplets that could be relevant in many different biological contexts.”
- Oxidative stress and diabetic retinopathy: Molecular mechanisms, pathogenetic role and therapeutic implications (2020, background): “defects bring about the accumulation of lipid droplets in glia that can be peroxided by the presence of ROS, causing the onset of neurodegeneration in retina [195].”