Loss of Glial Lazarillo, a Homolog of Apolipoprotein D, Reduces Lifespan and Stress Resistance in Drosophila

Abstract

The vertebrate Apolipoprotein D (ApoD) is a lipocalin secreted from subsets of neurons and glia during neural development and aging . A strong correlation exists between ApoD overexpression and numerous nervous system pathologies as well as obesity, diabetes, and many forms of cancer . However, the exact relationship between the function of ApoD and the pathophysiology of these diseases is still unknown. We have generated loss-of-function Drosophila mutants for the Glial Lazarillo (GLaz) gene , a homolog of ApoD in the fruit fly, mainly expressed in subsets of adult glial cells. The absence of GLaz reduces the organism's resistance to oxidative stress and starvation and shortens male lifespan. The mutant flies exhibit a smaller body mass due to a lower amount of neutral lipids stored in the fat body. Apoptotic neural cell death increases in aged flies or upon paraquat treatment, which also impairs neural function as assessed by behavioral tests. The higher sensitivity to oxidative stress and starvation and the reduced fat storage revert to control levels when a GFP-GLaz fusion protein is expressed under the control of the GLaz natural promoter. Finally, GLaz mutants have a higher concentration of lipid peroxidation products, pointing to a lipid peroxidation protection or scavenging as the mechanism of action for this lipocalin. In agreement with Walker et al. (, in this issue of Current Biology), who analyze the effects of overexpressing GLaz, we conclude that GLaz has a protective role in stress situations and that its absence reduces lifespan and accelerates neurodegeneration.

Expression and potential role of apolipoprotein D on the death–survival balance of human colorectal cancer cells under oxidative stress conditions

“…ApoD is upregulated by, and protects against, oxidative stress [9,13,15]. As reported here and in other works, ApoD expression is maintained at general low levels in tumor tissues, which, along with its positive regulation by growth arrest [38], supports the proposal made by several authors that ApoD is a tumor suppressor gene [30].…”

“…Inducing OS by treatment with the ROS generator paraquat (PQ), we have demonstrated a protective function of ApoD in the organism survival. This effect was associated with a role in regulating tissue homeostasis and in maintaining low levels of lipid peroxidation [13][14][15]. We have recently shown that ApoD contributes to reduce inflammation levels in ROS-injured tissues and promotes the clearance of lipid peroxides in cells [16,17].…”

“…The treatment of HT-29 cells with the ROS generator paraquat (PQ), which induces ApoD expression in these cells (Fig. 6a) and in a number of experimental models [13,15,16], shows a dramatic effect on both cell proliferation and cell death (Fig. 6c, d).…”

Apolipoprotein D mediates autocrine protection of astrocytes and controls their reactivity level, contributing to the functional maintenance of paraquat-challenged dopaminergic systems

“…Null mutants of ApoD or its homologous genes show an increased amount of peroxidated lipids in whole body fly extracts (Hull-Thompson et al, 2009;Sanchez et al, 2006) or in mouse brain homogenates (Ganfornina et al, 2008). Since lipid peroxidation in cellular membranes is a major sink for reactive oxygen species (ROS), a greater amount of peroxidated lipids can be due to a higher rate of production or to a slower rate of removal/recycling of the damaged membranes.…”

“…The homologues of ApoD in Drosophila, GLaz and NLaz, protect against oxidative damage and contribute significantly to the regulation of longevity (HullThompson et al, 2009;Ruiz et al, 2011;Sanchez et al, 2006;Walker et al, 2006). ApoD is in fact the most robust age dependent up-regulated gene in the brain, conserved across species (de Magalhaes et al, 2009;Loerch et al, 2008), and its expression is boosted by a collection of traumatic, pathological and degenerative nervous system conditions in humans (reviewed by Van Dijk et al, 2006), including Parkinson's disease (Ordonez et al, 2006;Song et al, 2009).…”