In Vivo Evidence for Lysosome Depletion and Impaired Autophagic Clearance in Hereditary Spastic Paraplegia Type SPG11

  1. Varga, Rita-Eva
  2. Khundadze, Mukhran
  3. Damme, Markus
  4. Nietzsche, Sandor
  5. Hoffmann, Birgit
  6. Stauber, Tobias ORCID logo
  7. Koch, Nicole
  8. Hennings, J. Christopher
  9. Franzka, Patricia
  10. Huebner, Antje K.
  11. Kessels, Michael M.
  12. Biskup, Christoph
  13. Jentsch, Thomas ORCID logo
  14. Qualmann, Britta
  15. Braulke, Thomas
  16. Kurth, Ingo
  17. Beetz, Christian
  18. Hübner, Christian A.

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WeightNameValue
1000 Titel
  • In Vivo Evidence for Lysosome Depletion and Impaired Autophagic Clearance in Hereditary Spastic Paraplegia Type SPG11
1000 Autor/in
  1. Varga, Rita-Eva |
  2. Khundadze, Mukhran |
  3. Damme, Markus |
  4. Nietzsche, Sandor |
  5. Hoffmann, Birgit |
  6. Stauber, Tobias |
  7. Koch, Nicole |
  8. Hennings, J. Christopher |
  9. Franzka, Patricia |
  10. Huebner, Antje K. |
  11. Kessels, Michael M. |
  12. Biskup, Christoph |
  13. Jentsch, Thomas |
  14. Qualmann, Britta |
  15. Braulke, Thomas |
  16. Kurth, Ingo |
  17. Beetz, Christian |
  18. Hübner, Christian A. |
1000 Erscheinungsjahr 2015
1000 LeibnizOpen
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2015-08-18
1000 Erschienen in
1000 Quellenangabe
  • 11(8): e1005454
1000 FRL-Sammlung
1000 Copyrightjahr
  • 2015
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1371/journal.pgen.1005454 |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4540459/ |
1000 Ergänzendes Material
  • http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1005454#sec020 |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • Hereditary spastic paraplegia (HSP) is characterized by a dying back degeneration of corticospinal axons which leads to progressive weakness and spasticity of the legs. SPG11 is the most common autosomal-recessive form of HSPs and is caused by mutations in SPG11. A recent in vitro study suggested that Spatacsin, the respective gene product, is needed for the recycling of lysosomes from autolysosomes, a process known as autophagic lysosome reformation. The relevance of this observation for hereditary spastic paraplegia, however, has remained unclear. Here, we report that disruption of Spatacsin in mice indeed causes hereditary spastic paraplegia-like phenotypes with loss of cortical neurons and Purkinje cells. Degenerating neurons accumulate autofluorescent material, which stains for the lysosomal protein Lamp1 and for p62, a marker of substrate destined to be degraded by autophagy, and hence appears to be related to autolysosomes. Supporting a more generalized defect of autophagy, levels of lipidated LC3 are increased in Spatacsin knockout mouse embryonic fibrobasts (MEFs). Though distinct parameters of lysosomal function like processing of cathepsin D and lysosomal pH are preserved, lysosome numbers are reduced in knockout MEFs and the recovery of lysosomes during sustained starvation impaired consistent with a defect of autophagic lysosome reformation. Because lysosomes are reduced in cortical neurons and Purkinje cells in vivo, we propose that the decreased number of lysosomes available for fusion with autophagosomes impairs autolysosomal clearance, results in the accumulation of undegraded material and finally causes death of particularly sensitive neurons like cortical motoneurons and Purkinje cells in knockout mice.
1000 Sacherschließung
lokal Spinal cord
lokal Purkinje cells
lokal Hippocampus
lokal Lysosomes
lokal Neurons
lokal Cerebellum
lokal Mouse models
lokal Autophagic cell death
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
  1. https://frl.publisso.de/adhoc/creator/VmFyZ2EsIFJpdGEtRXZh|https://frl.publisso.de/adhoc/creator/S2h1bmRhZHplLCBNdWtocmFu|https://frl.publisso.de/adhoc/creator/RGFtbWUsIE1hcmt1cw==|https://frl.publisso.de/adhoc/creator/TmlldHpzY2hlLCBTYW5kb3I=|https://frl.publisso.de/adhoc/creator/SG9mZm1hbm4sIEJpcmdpdA==|http://orcid.org/0000-0003-0727-6109|https://frl.publisso.de/adhoc/creator/S29jaCwgTmljb2xl|https://frl.publisso.de/adhoc/creator/SGVubmluZ3MsIEouIENocmlzdG9waGVy|https://frl.publisso.de/adhoc/creator/RnJhbnprYSwgUGF0cmljaWE=|https://frl.publisso.de/adhoc/creator/SHVlYm5lciwgQW50amUgSy4=|https://frl.publisso.de/adhoc/creator/S2Vzc2VscywgTWljaGFlbCBNLg==|https://frl.publisso.de/adhoc/creator/Qmlza3VwLCBDaHJpc3RvcGg=|http://orcid.org/0000-0002-3509-2553|https://frl.publisso.de/adhoc/creator/UXVhbG1hbm4sIEJyaXR0YQ==|https://frl.publisso.de/adhoc/creator/QnJhdWxrZSwgVGhvbWFz|https://frl.publisso.de/adhoc/creator/S3VydGgsIEluZ28=|https://frl.publisso.de/adhoc/creator/QmVldHosIENocmlzdGlhbg==|https://frl.publisso.de/adhoc/creator/SMO8Ym5lciwgQ2hyaXN0aWFuIEEu
1000 Label
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  1. Deutsche Forschungsgemeinschaft (DFG) |
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  1. HU 800/10-1; QU 116/6-2; KE685/4-2
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  1. 1000 joinedFunding-child
    1000 Förderer Deutsche Forschungsgemeinschaft (DFG) |
    1000 Förderprogramm -
    1000 Fördernummer HU 800/10-1; QU 116/6-2; KE685/4-2
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