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      Neuromelanin organelles are specialized autolysosomes that accumulate undegraded proteins and lipids in aging human brain and are likely involved in Parkinson’s disease

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          Abstract

          During aging, neuronal organelles filled with neuromelanin (a dark-brown pigment) and lipid bodies accumulate in the brain, particularly in the substantia nigra, a region targeted in Parkinson’s disease. We have investigated protein and lipid systems involved in the formation of these organelles and in the synthesis of the neuromelanin of human substantia nigra. Membrane and matrix proteins characteristic of lysosomes were found in neuromelanin-containing organelles at a lower number than in typical lysosomes, indicating a reduced enzymatic activity and likely impaired capacity for lysosomal and autophagosomal fusion. The presence of proteins involved in lipid transport may explain the accumulation of lipid bodies in the organelle and the lipid component in neuromelanin structure. The major lipids observed in lipid bodies of the organelle are dolichols with lower amounts of other lipids. Proteins of aggregation and degradation pathways were present, suggesting a role for accumulation by this organelle when the ubiquitin-proteasome system is inadequate. The presence of proteins associated with aging and storage diseases may reflect impaired autophagic degradation or impaired function of lysosomal enzymes. The identification of typical autophagy proteins and double membranes demonstrates the organelle’s autophagic nature and indicates that it has engulfed neuromelanin precursors from the cytosol. Based on these data, it appears that the neuromelanin-containing organelle has a very slow turnover during the life of a neuron and represents an intracellular compartment of final destination for numerous molecules not degraded by other systems.

          Biochemistry: Mummified organelles burying cellular debris

          Subcellular compartments in the brain that contain a dark brown pigment, known as neuromelanin, function like a warehouse for a broad array of molecules not degraded by other cellular cleanup systems. Luigi Zecca from the National Research Council of Italy and colleagues characterized all of the proteins and lipid molecules found inside neuromelanin-containing organelles of the substantia nigra, a region of the human brain that is lost in Parkinson’s disease. They identified many proteins involved in the breakdown of molecules — a sign that this organelle is a degradative organelle known as an autolysosome. Interestingly, the number of these proteins was lower than in a typical lysosome, suggestive of impaired degradative ability. The authors conclude that these neuromelanin-containing organelles accumulate pigment, lipids, proteins, and other compounds over the lifetime of a neuron, possibly leading to cellular dysfunction and disease.

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          Most cited references 135

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          LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing.

          Little is known about the protein constituents of autophagosome membranes in mammalian cells. Here we demonstrate that the rat microtubule-associated protein 1 light chain 3 (LC3), a homologue of Apg8p essential for autophagy in yeast, is associated to the autophagosome membranes after processing. Two forms of LC3, called LC3-I and -II, were produced post-translationally in various cells. LC3-I is cytosolic, whereas LC3-II is membrane bound. The autophagic vacuole fraction prepared from starved rat liver was enriched with LC3-II. Immunoelectron microscopy on LC3 revealed specific labelling of autophagosome membranes in addition to the cytoplasmic labelling. LC3-II was present both inside and outside of autophagosomes. Mutational analyses suggest that LC3-I is formed by the removal of the C-terminal 22 amino acids from newly synthesized LC3, followed by the conversion of a fraction of LC3-I into LC3-II. The amount of LC3-II is correlated with the extent of autophagosome formation. LC3-II is the first mammalian protein identified that specifically associates with autophagosome membranes.
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            Autophagy fights disease through cellular self-digestion.

            Autophagy, or cellular self-digestion, is a cellular pathway involved in protein and organelle degradation, with an astonishing number of connections to human disease and physiology. For example, autophagic dysfunction is associated with cancer, neurodegeneration, microbial infection and ageing. Paradoxically, although autophagy is primarily a protective process for the cell, it can also play a role in cell death. Understanding autophagy may ultimately allow scientists and clinicians to harness this process for the purpose of improving human health.
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              p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy.

              Protein degradation by basal constitutive autophagy is important to avoid accumulation of polyubiquitinated protein aggregates and development of neurodegenerative diseases. The polyubiquitin-binding protein p62/SQSTM1 is degraded by autophagy. It is found in cellular inclusion bodies together with polyubiquitinated proteins and in cytosolic protein aggregates that accumulate in various chronic, toxic, and degenerative diseases. Here we show for the first time a direct interaction between p62 and the autophagic effector proteins LC3A and -B and the related gamma-aminobutyrate receptor-associated protein and gamma-aminobutyrate receptor-associated-like proteins. The binding is mediated by a 22-residue sequence of p62 containing an evolutionarily conserved motif. To monitor the autophagic sequestration of p62- and LC3-positive bodies, we developed a novel pH-sensitive fluorescent tag consisting of a tandem fusion of the red, acid-insensitive mCherry and the acid-sensitive green fluorescent proteins. This approach revealed that p62- and LC3-positive bodies are degraded in autolysosomes. Strikingly, even rather large p62-positive inclusion bodies (2 microm diameter) become degraded by autophagy. The specific interaction between p62 and LC3, requiring the motif we have mapped, is instrumental in mediating autophagic degradation of the p62-positive bodies. We also demonstrate that the previously reported aggresome-like induced structures containing ubiquitinated proteins in cytosolic bodies are dependent on p62 for their formation. In fact, p62 bodies and these structures are indistinguishable. Taken together, our results clearly suggest that p62 is required both for the formation and the degradation of polyubiquitin-containing bodies by autophagy.
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                Author and article information

                Contributors
                luigi.zecca@itb.cnr.it
                Journal
                NPJ Parkinsons Dis
                NPJ Parkinsons Dis
                NPJ Parkinson's Disease
                Nature Publishing Group UK (London )
                2373-8057
                5 June 2018
                5 June 2018
                2018
                : 4
                Affiliations
                [1 ]ISNI 0000 0001 1940 4177, GRID grid.5326.2, Institute of Biomedical Technologies, , National Research Council of Italy, ; Segrate, Milan, Italy
                [2 ]IRCCS Don Carlo Gnocchi ONLUS Foundation, Milan, Italy
                [3 ]ISNI 0000 0004 1757 2822, GRID grid.4708.b, Department of Medical Biotechnology and Translational Medicine, , University of Milan, ; Segrate, Milan, Italy
                [4 ]ISNI 0000 0004 1762 5736, GRID grid.8982.b, Department of Chemistry, , University of Pavia, ; Pavia, Italy
                [5 ]ISNI 0000 0000 8499 1112, GRID grid.413734.6, Department of Psychiatry, Columbia University Medical Center, , New York State Psychiatric Institute, ; New York, NY USA
                [6 ]ISNI 0000 0001 2285 2675, GRID grid.239585.0, Department of Neurology, , Columbia University Medical Center, ; New York, NY USA
                [7 ]ISNI 0000 0001 2285 2675, GRID grid.239585.0, Department of Pharmacology, , Columbia University Medical Center, ; New York, NY USA
                Article
                50
                10.1038/s41531-018-0050-8
                5988730
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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