title: Glial lipid droplets and ROS induced by mitochondrial defects promote neurodegeneration.
abstract: 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.
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Lucy
authors.initials: L
authors.lastname: Liu
authors.affiliation: Structural and Computational Biology & Molecular Biophysics Graduate Program, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Hector
authors.initials: H
authors.lastname: Sandoval
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Manish
authors.initials: M
authors.lastname: Jaiswal
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
authors.forename: Elisenda
authors.initials: E
authors.lastname: Sanz
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Li
authors.affiliation: Center for Developmental Therapeutics, University of Washington, Seattle, WA, 98195, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Hui
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Brett H
authors.initials: BH
authors.lastname: Graham
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA; Center for Developmental Therapeutics, University of Washington, Seattle, WA, 98195, USA; Department of Pediatrics, University of Washington, Seattle, WA, 98195, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Quintana
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Structural and Computational Biology & Molecular Biophysics Graduate Program, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: hbellen@bcm.edu.
authors.forename: Hugo J
authors.initials: HJ
authors.lastname: Bellen
mesh_terms: D000818:Animals; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism; D066292:Lipid Droplets / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D051779:Sterol Regulatory Element Binding Proteins / Q000378:metabolism
chemical_list: C534449:Ndufs4 protein, mouse; D017382:Reactive Oxygen Species; D051779:Sterol Regulatory Element Binding Proteins; D048670:MAP Kinase Kinase 4; D042967:Electron Transport Complex I