Protecting cells by protecting their vulnerable lysosomes: Identification of a new mechanism for preserving lysosomal functional integrity upon oxidative stress
Publication Date
February 09, 2017
Authors
Raquel Pascua Maestro, Sergio Diez Hermano, Concepción Lillo, Maria D. Ganfornina, et al
Volume
13
Issue
2
Pages
e1006603
DOI
https://dx.plos.org/10.1371/journal.pgen.1006603
Publisher URL
http://journals.plos.org/plosgenetics/article?id=10.1371%2Fjournal.pgen.1006603
Scopus
85014096471
Mendeley
http://www.mendeley.com/research/protecting-cells-protecting-vulnerable-lysosomes-identification-new-mechanism-preserving-lysosomal-f
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Mendeley | Further Information

{"title"=>"Protecting cells by protecting their vulnerable lysosomes: Identification of a new mechanism for preserving lysosomal functional integrity upon oxidative stress", "type"=>"journal", "authors"=>[{"first_name"=>"Raquel", "last_name"=>"Pascua-Maestro", "scopus_author_id"=>"56611931100"}, {"first_name"=>"Sergio", "last_name"=>"Diez-Hermano", "scopus_author_id"=>"56602914100"}, {"first_name"=>"Concepción", "last_name"=>"Lillo", "scopus_author_id"=>"7003657411"}, {"first_name"=>"Maria D.", "last_name"=>"Ganfornina", "scopus_author_id"=>"6701435656"}, {"first_name"=>"Diego", "last_name"=>"Sanchez", "scopus_author_id"=>"26631443600"}], "year"=>2017, "source"=>"PLoS Genetics", "identifiers"=>{"pmid"=>"28182653", "scopus"=>"2-s2.0-85014096471", "pui"=>"614651192", "issn"=>"15537404", "isbn"=>"1111111111", "doi"=>"10.1371/journal.pgen.1006603", "sgr"=>"85014096471"}, "id"=>"13516343-c10b-317d-95b4-4058e5288fc3", "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.", "link"=>"http://www.mendeley.com/research/protecting-cells-protecting-vulnerable-lysosomes-identification-new-mechanism-preserving-lysosomal-f", "reader_count"=>18, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>3, "Researcher"=>3, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>4, "Student > Master"=>2, "Student > Bachelor"=>4}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>3, "Researcher"=>3, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>4, "Student > Master"=>2, "Student > Bachelor"=>4}, "reader_count_by_subject_area"=>{"Environmental Science"=>1, "Biochemistry, Genetics and Molecular Biology"=>1, "Medicine and Dentistry"=>1, "Agricultural and Biological Sciences"=>8, "Neuroscience"=>6, "Pharmacology, Toxicology and Pharmaceutical Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Neuroscience"=>{"Neuroscience"=>6}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>8}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}, "Environmental Science"=>{"Environmental Science"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"Canada"=>1, "Belgium"=>1}, "group_count"=>0}

Scopus | Further Information

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