Mitochondrial impairment and oxidative stress compromise autophagosomal degradation of α‐synuclein in oligodendroglial cells
Abstract
α‐Synuclein (α‐syn)‐containing glial cytoplasmic inclusions originating in oligodendrocytes are characteristically observed in multiple system atrophy. The mechanisms of glial cytoplasmic inclusion formation remain rather elusive. α‐Syn over‐expression, uptake from the environment, oxidative stress or impairment of the proteolytic degradation systems have been discussed. Here, we investigated whether in oligodendrocytes autophagy plays a major role in the degradation and aggregation of endogenously expressed α‐syn and of α‐syn taken up from the extracellular environment. Furthermore, we studied whether in cells with impaired mitochondria the accumulation and aggregation of exogenously added α‐syn is promoted. Using primary cultures of rat brain oligodendrocytes and an oligodendroglial cell line, genetically engineered to express green fluorescent protein–microtubule‐associated light chain 3 with or without α‐syn to monitor the autophagic flux, we demonstrate that both exogenously applied α‐syn and α‐syn stably expressed endogenously are effectively degraded by autophagy and do not affect the autophagic flux per se. Mitochondrial impairment with the protonophore carbonyl cyanide 3‐chlorophenylhydrazone or 3‐nitropropionic acid disturbs the autophagic pathway and leads to the accumulation of exogenously applied α‐syn and enhances its propensity to form aggregates intracellularly. Thus, mitochondrial dysfunction and oxidative stress, which occur over time and are significant pathological features in synucleinopathies, have an impact on the autophagic pathway and participate in pathogenesis. image Glial cytoplasmic inclusions are characteristically observed in multiple system atrophy, their occurrence might be related to failure in protein degradation systems. Here, we show that in oligodendrocytes autophagy is the major route of α‐synuclein degradation which is either endogenously expressed or added exogenously (1, 2). Mitochondrial impairment (3) disturbs the autophagic flux and leads to the accumulation of exogenously applied α‐synuclein, and enhances its propensity to form aggregates intracellulary (4).
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Accumulation of SNCA inclusions in oligodendrocytes is exacerbated by autophagy inhibition, either pharmacologically with chloroquine or genetically by MIR101 overexpression.
“and the accumulation of these inclusions is exacerbated by autophagy inhibition, either pharmacologically with chloroquine or genetically by MIR101 overexpression [12,450,454].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [450]
Rapamycin fails to enhance recovery after spinal cord contusion in mice despite effective stimulation of autophagy in oligodendrocytes.
“but rapamycin fails to enhance recovery [449] despite effective stimulation of autophagy in these cells [449–451].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [450]
Cites
Methods in Mammalian Autophagy Research
Mizushima, N., Yoshimori, T., & Levine, B. (2010) · Cell · doi:10.1016/j.cell.2010.01.028 · Cited by 4,497 · see citing works
Parkin is recruited selectively to impaired mitochondria and promotes their autophagy
Narendra, D., Tanaka, A., Suen, D.-F., & Youle, R. J. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200809125 · Cited by 4,026 · see citing works
Guidelines for the use and interpretation of assays for monitoring autophagy
Klionsky, D. J., Abdalla, F. C., Abeliovich, H., Abraham, R. T., Acevedo-Arozena, A., Adeli, K., Agholme, L., Agnello, M., Agostinis, P., Aguirre-Ghiso, J. A., et al. (2012) · Autophagy · doi:10.4161/auto.19496 · Cited by 3,996 · see citing works
Oxidative stress and neurodegeneration: where are we now?
Halliwell, B. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.03907.x · Cited by 2,614 · see citing works
Oxidative stress and autophagy: The clash between damage and metabolic needs
Filomeni, G., De Zio, D., & Cecconi, F. (2015) · Cell Death & Differentiation · doi:10.1038/cdd.2014.150 · Cited by 2,195 · see citing works
Impaired Degradation of Mutant α-Synuclein by Chaperone-Mediated Autophagy
Cuervo, A. M., Stefanis, L., Fredenburg, R., Lansbury, P. T., & Sulzer, D. (2004) · Science · doi:10.1126/science.1101738 · Cited by 2,024 · cited 1× · see citing works
“For example, soluble (so) a-syn has been described to be degraded by the UPS, autophagy, and also by chaperone-mediated autophagy (Tofaris et al. 2001; Webb et al. 2003; Cuervo et al. 2004; Vogiatzi et al. 2008).”
BackgroundSelective autophagy mediated by autophagic adapter proteins
Johansen, T., & Lamark, T. (2011) · Autophagy · doi:10.4161/auto.7.3.14487 · Cited by 1,730 · see citing works
Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein
Desplats, P., Lee, H.-J., Bae, E.-J., Patrick, C., Rockenstein, E., Crews, L., Spencer, B., Masliah, E., & Lee, S.-J. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0903691106 · Cited by 1,485 · see citing works
α-Synuclein Is Degraded by Both Autophagy and the Proteasome
Webb, J. L., Ravikumar, B., Atkins, J., Skepper, J. N., & Rubinsztein, D. C. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300227200 · Cited by 1,429 · see citing works
HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS.
Pandey, U. B., Nie, Z., Batlevi, Y., McCray, B. A., Ritson, G. P., Nedelsky, N. B., Schwartz, S. L., DiProspero, N. A., Knight, M. A., Schuldiner, O., et al. (2007) · Nature · doi:10.1038/nature05853 · Cited by 1,234 · see citing works
Luk, K. C., Kehm, V. M., Zhang, B., O’Brien, P., Trojanowski, J. Q., & Lee, V. M. ‐. (2012) · The Journal of Experimental Medicine · doi:10.1084/jem.20112457 · Cited by 1,087 · see citing works
Lee, H.-J., Suk, J.-E., Patrick, C., Bae, E.-J., Cho, J.-H., Rho, S., Hwang, D., Masliah, E., & Lee, S.-J. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.081125 · Cited by 877 · see citing works
Hansen, C., Angot, E., Bergström, A.-L., Steiner, J. A., Pieri, L., Paul, G., Outeiro, T. F., Melki, R., Kallunki, P., Fog, K., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci43366 · Cited by 842 · see citing works
α-Synuclein impairs macroautophagy: implications for Parkinson’s disease
Winslow, A. R., Chen, C.-W., Corrochano, S., Acevedo-Arozena, A., Gordon, D. E., Peden, A. A., Lichtenberg, M., Menzies, F. M., Ravikumar, B., Imarisio, S., et al. (2010) · Journal of Cell Biology · doi:10.1083/jcb.201003122 · Cited by 825 · see citing works
Prion-like mechanisms in neurodegenerative diseases
Frost, B., & Diamond, M. I. (2010) · Nature Reviews Neuroscience · doi:10.1038/nrn2786 · Cited by 776 · see citing works
α-Synuclein Promotes Mitochondrial Deficit and Oxidative Stress
Hsu, L. J., Sagara, Y., Arroyo, A., Rockenstein, E. M., Sisk, A., Mallory, M. E., Wong, J., Takenouchi, T., Hashimoto, M., & Masliah, E. (2000) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)64553-1 · Cited by 716 · see citing works
Vogiatzi, T., Xilouri, M., Vekrellis, K., & Stefanis, L. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m801992200 · Cited by 683 · see citing works
Basic mechanisms of neurodegeneration: a critical update
Jellinger, K. A. (2010) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2010.01010.x · Cited by 608 · see citing works
Fighting neurodegeneration with rapamycin: mechanistic insights
Bové, J., Martínez‐Vicente, M., & Vila, M. (2011) · Nature reviews. Neuroscience · doi:10.1038/nrn3068 · Cited by 525 · see citing works
Targeting Proteins for Destruction by the Ubiquitin System: Implications for Human Pathobiology
Schwartz, A. L., & Ciechanover, A. J. (2008) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.051208.165340 · Cited by 491 · see citing works
Aggrephagy: Selective Disposal of Protein Aggregates by Macroautophagy
Lamark, T., & Johansen, T. (2012) · International Journal of Cell Biology · doi:10.1155/2012/736905 · Cited by 490 · see citing works
Assembly-dependent endocytosis and clearance of extracellular a-synuclein
Lee, H.-J., Suk, J.-E., Bae, E.-J., Lee, J.-H., Paik, S. R., & Lee, S.-J. (2008) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2008.01.017 · Cited by 470 · see citing works
The propagation of prion-like protein inclusions in neurodegenerative diseases
Goedert, M., Clavaguera, F., & Tolnay, M. (2010) · Trends in Neurosciences · doi:10.1016/j.tins.2010.04.003 · Cited by 451 · see citing works
Clearance of α-Synuclein Oligomeric Intermediates via the Lysosomal Degradation Pathway
Lee, H.-J., Khoshaghideh, F., Patel, S., & Lee, S.-J. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.3809-03.2004 · Cited by 445 · see citing works
Tofaris, G. K., Layfield, R., & Spillantini, M. G. (2001) · FEBS Letters · doi:10.1016/s0014-5793(01)03115-5 · Cited by 363 · see citing works
Dissecting the dynamic turnover of GFP-LC3 in the autolysosome
Ni, H., Bockus, A. B., Wozniak, A. L., Jones, K., Weinman, S. A., Yin, X., & Ding, W. (2011) · Autophagy · doi:10.4161/auto.7.2.14181 · Cited by 350 · see citing works
The PINK1/Parkin-mediated mitophagy is compromised by PD-associated mutations
Geisler, S., Holmström, K. M., Treis, A., Skujat, D., Weber, S. S., Fiesel, F. C., Kahle, P. J., & Springer, W. (2010) · Autophagy · doi:10.4161/auto.6.7.13286 · Cited by 311 · cited 2× · see citing works
“…a protonophore which causes mitochondrial depolarization and has been demonstrated to trigger Parkin-dependent mitophagy (Narendra et al. 2008; Geisler et al. 2010), or with 3- NP, which is an inhibitor of succinate dehydrogenase and has been shown to exacerbate motor deficits in a mouse…”
BackgroundBecker, C. G., Artola, A., Gerardy‐Schahn, R., Becker, T., Welzl, H., & Schachner, M. (1996) · Journal of Neuroscience Research · doi:10.1002/(sici)1097-4547(19960715)45:2 · Cited by 304 · see citing works
How do delays in treatment affect patient prognosis in head and neck cancer?
Mohamedbhai, H., Thomas, S., Ali, S. R., Whitley, S., Liew, C., Sadiq, Z., Kalavrezos, N., & Hutchinson, I. (2017) · British Journal of Oral and Maxillofacial Surgery · doi:10.1016/j.bjoms.2017.08.058 · Cited by 303 · see citing works
Alpha-synuclein and Protein Degradation Systems: a Reciprocal Relationship
Xilouri, M., Brekk, O. R., & Stefanis, L. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8341-2 · Cited by 299 · see citing works
Are synucleinopathies prion-like disorders?
Angot, É., Steiner, J. A., Hansen, C., Li, J., & Brundin, P. (2010) · The Lancet Neurology · doi:10.1016/s1474-4422(10)70213-1 · Cited by 283 · see citing works
Jang, A., Lee, H., Suk, J., Jung, J., Kim, K., & Lee, S. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.06695.x · Cited by 281 · see citing works
Alpha‐synuclein transfers from neurons to oligodendrocytes
Reyes, J. F., Rey, N. L., Bousset, L., Melki, R., Brundin, P., & Angot, É. (2013) · Glia · doi:10.1002/glia.22611 · Cited by 278 · see citing works
NEUHOFF, V., Philipp, K., Zimmer, H.-G., & Mesecke, S. (1979) · Hoppe-Seyler´s Zeitschrift für physiologische Chemie · doi:10.1515/bchm2.1979.360.2.1657 · Cited by 230 · see citing works
Stefanova, N., Reindl, M., Neumann, M., Haass, C., Poewe, W., Kahle, P. J., & Wenning, G. K. (2005) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)62307-3 · Cited by 208 · see citing works
A new method for purification of recombinant human α-synuclein in Escherichia coli
Huang, C., Ren, G., Zhou, H., & Wang, C.-C. (2005) · Protein Expression and Purification · doi:10.1016/j.pep.2005.02.014 · Cited by 183 · see citing works
Norris, E. H., Giasson, B. I., Ischiropoulos, H., & Lee, V. M. ‐. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m212436200 · Cited by 180 · see citing works
Assessment of α-Synuclein Secretion in Mouse and Human Brain Parenchyma
Emmanouilidou, E., Elenis, D., Papasilekas, T., Stranjalis, G., Gerozissis, K., Ioannou, P. C., & Vekrellis, K. (2011) · PLoS ONE · doi:10.1371/journal.pone.0022225 · Cited by 163 · see citing works
Multiple system atrophy: a clinical and neuropathological perspective
Ubhi, K. K., Low, P. A., & Masliah, E. (2011) · Trends in Neurosciences · doi:10.1016/j.tins.2011.08.003 · Cited by 159 · see citing works
Papp–Lantos inclusions and the pathogenesis of multiple system atrophy: an update
Jellinger, K. A., & Lantos, P. L. (2010) · Acta Neuropathologica · doi:10.1007/s00401-010-0672-3 · Cited by 144 · see citing works
Interaction between pathogenic proteins in neurodegenerative disorders
Jellinger, K. A. (2011) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2011.01507.x · Cited by 128 · see citing works
Padman, B. S., Bach, M., Lucarelli, G., Prescott, M., & Ramm, G. (2013) · Autophagy · doi:10.4161/auto.26557 · Cited by 106 · see citing works
Inclusion body formation, macroautophagy, and the role of HDAC6 in neurodegeneration
Richter‐Landsberg, C., & Leyk, J. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1158-x · Cited by 104 · see citing works
Self-citationGlial cell death induced by overexpression of α‐synuclein
Stefanova, N., Klimaschewski, L., Poewe, W., Wenning, G. K., & Reindl, M. (2001) · Journal of Neuroscience Research · doi:10.1002/jnr.1171 · Cited by 93 · see citing works
Kisos, H., Pukaß, K., Ben‐Hur, T., Richter‐Landsberg, C., & Sharon, R. (2012) · PLoS ONE · doi:10.1371/journal.pone.0046817 · Cited by 90 · see citing works
Self-citation17-AAG Induces Cytoplasmic α-Synuclein Aggregate Clearance by Induction of Autophagy
Riedel, M., Goldbaum, O., Schwarz, L., Schmitt, S., & Richter-Landsberg, C. (2010) · PLoS ONE · doi:10.1371/journal.pone.0008753 · Cited by 87 · see citing works
Self-citationStahnke, T., Richter‐Landsberg, C., Stadelmann, C., Netzler, A., & Brück, W. (2007) · Journal of Molecular Neuroscience · doi:10.1007/s12031-007-0005-8 · Cited by 86 · see citing works
Self-citationSchwarz, L., Goldbaum, O., Bergmann, M., Probst‐Cousin, S., & Richter‐Landsberg, C. (2012) · Journal of Molecular Neuroscience · doi:10.1007/s12031-012-9733-5 · Cited by 82 · see citing works
Self-citationGoldbaum, O., & Richter‐Landsberg, C. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.1307-04.2004 · Cited by 75 · see citing works
Self-citationGoldbaum, O., Oppermann, M., Handschuh, M., Dabir, D. V., Zhang, B., Forman, M. S., Trojanowski, J. Q., Lee, V. M. ‐., & Richter‐Landsberg, C. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-26-08872.2003 · Cited by 73 · see citing works
Self-citationAlteration of autophagosomal proteins in the brain of multiple system atrophy
Tanji, K., Odagiri, S., Maruyama, A., Mori, F., Kakita, A., Takahashi, H., & Wakabayashi, K. (2012) · Neurobiology of Disease · doi:10.1016/j.nbd.2012.08.017 · Cited by 64 · see citing works
Solesio, M. E., Sáez-Atiénzar, S., Jordán, J., & Galindo, M. F. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2012.01994.x · Cited by 61 · see citing works
CCCP induces autophagy in an AMPK-independent manner
Kwon, K.-Y., Viollet, B., & Yoo, O. J. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.11.038 · Cited by 55 · see citing works
Riedel, M. J., Goldbaum, O., & Richter‐Landsberg, C. (2009) · Journal of Molecular Neuroscience · doi:10.1007/s12031-009-9190-y · Cited by 48 · see citing works
Self-citationPukaß, K., & Richter‐Landsberg, C. (2013) · Journal of Molecular Neuroscience · doi:10.1007/s12031-013-0154-x · Cited by 48 · see citing works
Self-citationEffects of rapamycin and TOR on aging and memory: implications for Alzheimer’s disease
Santos, R. X., Correia, S. C., Cardoso, S., Carvalho, C., Santos, M. S., & Moreira, P. I. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07262.x · Cited by 45 · see citing works
Chiba, Y., Takei, S., Kawamura, N., Kawaguchi, Y., Sasaki, K., Hasegawa‐Ishii, S., Furukawa, A., Hosokawa, M., & Shimada, A. (2011) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.2011.01229.x · Cited by 44 · see citing works
Martínez‐Vicente, M., & Vila, M. (2013) · Experimental Neurology · doi:10.1016/j.expneurol.2013.03.005 · Cited by 44 · see citing works
Rockenstein, E. M., Ubhi, K. K., Inglis, C. A., Mante, M., Patrick, C., Adame, A., & Masliah, E. (2012) · Neuroreport · doi:10.1097/wnr.0b013e3283509842 · Cited by 31 · see citing works
Tsuboi, K., Grzesiak, J. J., Bouvet, M., Hashimoto, M., Masliah, E., & Shults, C. W. (2005) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2005.03.001 · Cited by 29 · see citing works
Seiberlich, V., Borchert, J., Zhukareva, V. A., & Richter‐Landsberg, C. (2013) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-013-9622-8 · Cited by 27 · see citing works
Self-citationPereira, G. J. S., Tressoldi, N., Hirata, H., et al. (2013) · Neurochemical Research · doi:10.1007/s11064-013-1154-5 · Cited by 16 · see citing works
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“Oligodendrocytes Activates [450] Activates [530] MIR101 [12]”
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- Authors
- Pukaß, K., Goldbaum, O., & Richter‐Landsberg, C.
- Affiliations
- Carl von Ossietzky Universität Oldenburg (DE)
- Corresponding author
- Richter‐Landsberg, Christiane
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2015-08-12
- Volume
- 135
- Issue
- 1
- Pages
- 194-205
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W1521681896
- Cited by
- 49
- References
- 62
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 3 · 2023: 3 · 2022: 1 · 2021: 6 · 2020: 4 · 2019: 8 · 2018: 7 · 2017: 3 · 2016: 5
- FWCI
- 3.53
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (RI 384/16‐2)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- alpha-synuclein, autophagy, oligodendrocytes, mitochondrial dysfunction, oxidative stress, glial cytoplasmic inclusions, multiple system atrophy, protein aggregation, autophagic flux, carbonyl cyanide 3-chlorophenylhydrazone, 3-nitropropionic acid, synucleinopathies, protein degradation
- MeSH terms
- Animals, Autophagy, Cells, Cultured, Cytoplasm, Mitochondria, Nerve Tissue Proteins, Nitro Compounds, Oligodendroglia, Propionates, Oxidative Stress, Multiple System Atrophy, Rats, alpha-Synuclein
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