Abstract
Environmental insults such as oxidative stress can damage cell membranes. Lysosomes are particularly sensitive to membrane permeabilization since their function depends on intraluminal acidic pH and requires stable membrane-dependent proton gradients. Among the catalog of oxidative stress-responsive genes is the Lipocalin Apolipoprotein D (ApoD), an extracellular lipid binding protein endowed with antioxidant capacity. Within the nervous system, cell types in the defense frontline, such as astrocytes, secrete ApoD to help neurons cope with the challenge. The protecting role of ApoD is known from cellular to organism level, and many of its downstream effects, including optimization of autophagy upon neurodegeneration, have been described. However, we still cannot assign a cellular mechanism to ApoD gene that explains how this protection is accomplished. Here we perform a comprehensive analysis of ApoD intracellular traffic and demonstrate its role in lysosomal pH homeostasis upon paraquat-induced oxidative stress. By combining single-lysosome in vivo pH measurements with immunodetection, we demonstrate that ApoD is endocytosed and targeted to a subset of vulnerable lysosomes in a stress-dependent manner. ApoD is functionally stable in this acidic environment, and its presence is sufficient and necessary for lysosomes to recover from oxidation-induced alkalinization, both in astrocytes and neurons. This function is accomplished by preventing lysosomal membrane permeabilization. Two lysosomal-dependent biological processes, myelin phagocytosis by astrocytes and optimization of neurodegeneration-triggered autophagy in a Drosophila in vivo model, require ApoD-related Lipocalins. Our results uncover a previously unknown biological function of ApoD, member of the finely regulated and evolutionary conserved gene family of extracellular Lipocalins. They set a lipoprotein-mediated regulation of lysosomal membrane integrity as a new mechanism at the hub of many cellular functions, critical for the outcome of a wide variety of neurodegenerative diseases. These results open therapeutic opportunities by providing a route of entry and a repair mechanism for lysosomes in pathological situations.
Highlights
Lysosomes are acidic intracellular vesicles that provide an optimal physicochemical milieu for enzymatic activities, most of them catabolic, which need to be controlled
Using the Drosophila retina as a model system to assay neurodegeneration, we previously described that Type I Spinocerebellar Ataxia (SCA1) concurs with autophagic stress, showing an excessive or imbalanced induction of autophagy where autophagosome turnover is unable to keep pace with its formation [37]
Glial Lazarillo (GLaz), a Drosophila homologue of Apolipoprotein D (ApoD) expressed by subsets of glial cells in the fly nervous system, has epistatic relationship with autophagy genes and optimizes clearance of aggregation-prone proteins such as the polyglutaminated form of human Ataxin 1 that is responsible for the SCA1 phenotype [37]
Summary
Lysosomes are acidic intracellular vesicles that provide an optimal physicochemical milieu for enzymatic activities, most of them catabolic, which need to be controlled. A well-recognized lysosomal function is the degradation and recycling of defective cellular material through autophagy, and of extracellular material that reach lysosomes by endocytosis or phagocytosis. Documented functions such as energy and nutrient sensing, secretion, plasma membrane repair, immune response and cell death, reveal lysosomes as sophisticated organelles controlling fine decisions in the life of a cell [reviewed by 1,2,3]. Lysosome function is essential for human health, as clearly shown by the existence of numerous Lysosomal Storage Diseases [reviewed by 4], inherited metabolic disorders that affect a variety of tissues and organs and are devastating for the nervous system. Proper lysosomal and autophagic functions are essential for the survival of postmitotic neurons, for the phagocytic activity of microglia and for the myelination process performed by Schwann cells and oligodendrocytes [8,9,10,11]
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