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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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          Meta-analysis of age-related gene expression profiles identifies common signatures of aging.

          Numerous microarray studies of aging have been conducted, yet given the noisy nature of gene expression changes with age, elucidating the transcriptional features of aging and how these relate to physiological, biochemical and pathological changes remains a critical problem. We performed a meta-analysis of age-related gene expression profiles using 27 datasets from mice, rats and humans. Our results reveal several common signatures of aging, including 56 genes consistently overexpressed with age, the most significant of which was APOD, and 17 genes underexpressed with age. We characterized the biological processes associated with these signatures and found that age-related gene expression changes most notably involve an overexpression of inflammation and immune response genes and of genes associated with the lysosome. An underexpression of collagen genes and of genes associated with energy metabolism, particularly mitochondrial genes, as well as alterations in the expression of genes related to apoptosis, cell cycle and cellular senescence biomarkers, were also observed. By employing a new method that emphasizes sensitivity, our work further reveals previously unknown transcriptional changes with age in many genes, processes and functions. We suggest these molecular signatures reflect a combination of degenerative processes but also transcriptional responses to the process of aging. Overall, our results help to understand how transcriptional changes relate to the process of aging and could serve as targets for future studies. http://genomics.senescence.info/uarrays/signatures.html. Supplementary data are available at Bioinformatics online.
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            Alpha-crystallin can function as a molecular chaperone.

            J. Horwitz (1992)
            The alpha-crystallins (alpha A and alpha B) are major lens structural proteins of the vertebrate eye that are related to the small heat shock protein family. In addition, crystallins (especially alpha B) are found in many cells and organs outside the lens, and alpha B is overexpressed in several neurological disorders and in cell lines under stress conditions. Here I show that alpha-crystallin can function as a molecular chaperone. Stoichiometric amounts of alpha A and alpha B suppress thermally induced aggregation of various enzymes. In particular, alpha-crystallin is very efficient in suppressing the thermally induced aggregation of beta- and gamma-crystallins, the two other major mammalian structural lens proteins. alpha-Crystallin was also effective in preventing aggregation and in refolding guanidine hydrochloride-denatured gamma-crystallin, as judged by circular dichroism spectroscopy. My results thus indicate that alpha-crystallin refracts light and protects proteins from aggregation in the transparent eye lens and that in nonlens cells alpha-crystallin may have other functions in addition to its capacity to suppress aggregation of proteins.
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              Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson's disease.

              In idiopathic Parkinson's disease massive cell death occurs in the dopamine-containing substantia nigra. A link between the vulnerability of nigral neurons and the prominent pigmentation of the substantia nigra, though long suspected, has not been proved. This possibility is supported by evidence that N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its metabolite MPP+, the latter of which causes destruction of nigral neurons, bind to neuromelanin. We have directly tested this hypothesis by a quantitative analysis of neuromelanin-pigmented neurons in control and parkinsonian midbrains. The findings demonstrate first that the dopamine-containing cell groups of the normal human midbrain differ markedly from each other in the percentage of neuromelanin-pigmented neurons they contain. Second, the estimated cell loss in these cell groups in Parkinson's disease is directly correlated (r = 0.97, P = 0.0057) with the percentage of neuromelanin-pigmented neurons normally present in them. Third, within each cell group in the Parkinson's brains, there is greater relative sparing of non-pigmented than of neuromelanin-pigmented neurons. This evidence suggests a selective vulnerability of the neuromelanin-pigmented subpopulation of dopamine-containing mesencephalic neurons in Parkinson's disease.
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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
                : 17
                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
                Author information
                http://orcid.org/0000-0003-1230-1129
                http://orcid.org/0000-0001-6218-8393
                http://orcid.org/0000-0001-7632-0439
                Article
                50
                10.1038/s41531-018-0050-8
                5988730
                29900402
                79fee610-3c77-4f74-8f1e-b0658ec83140
                © 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/.

                History
                : 14 December 2017
                : 10 April 2018
                : 17 April 2018
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