BAX channel activity mediates lysosomal disruption linked to Parkinson disease
Open accessAbstract
Lysosomal disruption is increasingly regarded as a major pathogenic event in Parkinson disease (PD). A reduced number of intraneuronal lysosomes, decreased levels of lysosomal-associated proteins and accumulation of undegraded autophagosomes (AP) are observed in PD-derived samples, including fibroblasts, induced pluripotent stem cell-derived dopaminergic neurons, and post-mortem brain tissue. Mechanistic studies in toxic and genetic rodent PD models attribute PD-related lysosomal breakdown to abnormal lysosomal membrane permeabilization (LMP). However, the molecular mechanisms underlying PD-linked LMP and subsequent lysosomal defects remain virtually unknown, thereby precluding their potential therapeutic targeting. Here we show that the pro-apoptotic protein BAX (BCL2-associated X protein), which permeabilizes mitochondrial membranes in PD models and is activated in PD patients, translocates and internalizes into lysosomal membranes early following treatment with the parkinsonian neurotoxin MPTP, both in vitro and in vivo, within a time-frame correlating with LMP, lysosomal disruption, and autophagosome accumulation and preceding mitochondrial permeabilization and dopaminergic neurodegeneration. Supporting a direct permeabilizing effect of BAX on lysosomal membranes, recombinant BAX is able to induce LMP in purified mouse brain lysosomes and the latter can be prevented by pharmacological blockade of BAX channel activity. Furthermore, pharmacological BAX channel inhibition is able to prevent LMP, restore lysosomal levels, reverse AP accumulation, and attenuate mitochondrial permeabilization and overall nigrostriatal degeneration caused by MPTP, both in vitro and in vivo. Overall, our results reveal that PD-linked lysosomal impairment relies on BAX-induced LMP, and point to small molecules able to block BAX channel activity as potentially beneficial to attenuate both lysosomal defects and neurodegeneration occurring in PD.
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Primary LMP has been documented in an animal model of Parkinson's disease.
“as well in an animal model of Parkinson's disease [764].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [764]
In other experimental settings, lysosomes are permeabilized before mitochondria via a mechanism that optionally involves BAX recruitment to the lysosomal membrane followed by activation of its pore-forming activity.
“In other experimental settings, however, lysosomes are permeabilized before mitochondria [752, 760, 761], via a mechanism that optionally involves BAX recruitment to the lysosomal membrane followed by the activation of its pore-forming activity [762–765].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [764]
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Cites
Dauer, W., & Przedborski, S. (2003) · Neuron · doi:10.1016/s0896-6273(03)00568-3 · Cited by 5,469 · see citing works
Autophagic cell death: the story of a misnomer
Kroemer, G., & Levine, B. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2529 · Cited by 1,453 · see citing works
Protocol for the MPTP mouse model of Parkinson's disease
Jackson-Lewis, V. R., & Przedborski, S. (2007) · Nature Protocols · doi:10.1038/nprot.2006.342 · Cited by 1,118 · see citing works
Pathogenic Lysosomal Depletion in Parkinson's Disease
Dehay, B., Bové, J., Rodríguez-Muela, N., Perier, C., Recasens, A., Boya, P., & Vila, M. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.1920-10.2010 · Cited by 825 · see citing works
Self-citationTFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity
Decressac, M., Mattsson, B., Weikop, P., Lundblad, M., Jakobsson, J., & Björklund, A. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1305623110 · Cited by 753 · see citing works
Kirik, D., Rosenblad, C., Bürger, C., Lundberg, C., Johansen, T. E., Muzyczka, N., Mandel, R. J., & Björklund, A. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-07-02780.2002 · Cited by 730 · see citing works
Hartmann, A., Hunot, S., Michel, P. P., Muriel, M., Vyas, S., Faucheux, B. A., Prigent, A., Turmel, H., Srinivasan, A. N., Ruberg, M., et al. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.040556597 · Cited by 717 · see citing works
Bcl-xL Retrotranslocates Bax from the Mitochondria into the Cytosol
Edlich, F., Banerjee, S., Suzuki, M., Cleland, M. M., Arnoult, D., Wang, C., Neutzner, A., Tjandra, N., & Youle, R. J. (2011) · Cell · doi:10.1016/j.cell.2011.02.034 · Cited by 630 · see citing works
Sànchez-Dànes, A., Richaud-Patin, Y., Carballo-Carbajal, I., Jiménez-Delgado, S., Caig, C., Mora, S., Guglielmo, C. D., Ezquerra, M., Patel, B., Giralt, A., et al. (2012) · EMBO Molecular Medicine · doi:10.1002/emmm.201200215 · Cited by 576 · see citing works
Self-citation[16] Isolation of subcellular organelles
Storrie, B., & Amadden, E. (1990) · Methods in Enzymology · doi:10.1016/0076-6879(90)82018-w · Cited by 555 · see citing works
Targeting programmed cell death in neurodegenerative diseases
Vila, M., & Przedborski, S. (2003) · Nature reviews. Neuroscience · doi:10.1038/nrn1100 · Cited by 545 · see citing works
Self-citationFighting 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
Self-citationThe apoptosis/autophagy paradox: autophagic vacuolization before apoptotic death
González‐Polo, R. A., Boya, P., Pauleau, A., Jalil, A., Larochette, N., Souquère, S., Eskelinen, E., Pierron, G., Säftig, P., & Kroemer, G. (2005) · Journal of Cell Science · doi:10.1242/jcs.02447 · Cited by 525 · see citing works
Chu, Y., Dodiya, H. B., Aebischer, P., Olanow, C. W., & Kordower, J. H. (2009) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.05.023 · Cited by 420 · see citing works
Mitochondrial membrane permeabilization in neuronal injury
Galluzzi, L., Blomgren, K., & Kroemer, G. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2665 · Cited by 418 · see citing works
Dehay, B., Ramı́rez, A., Martínez‐Vicente, M., Perier, C., Canron, M., Doudnikoff, É., Vital, A., Vila, M., Klein, C., & Bézard, E. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1112368109 · Cited by 381 · see citing works
Self-citationVila, M., Jackson-Lewis, V. R., Vukosavić, S., Djaldetti, R., Liberatore, G. T., Offen, D., Korsmeyer, S. J., & Przedborski, S. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.051633998 · Cited by 372 · see citing works
Self-citationLysosomal impairment in Parkinson's disease
Dehay, B., Martinez‐Vicente, M., Caldwell, G. A., Caldwell, K. A., Yue, Z., Cookson, M. R., Klein, C., Vila, M., & Bezard, E. (2013) · Movement Disorders · doi:10.1002/mds.25462 · Cited by 340 · see citing works
Self-citationViswanath, V., Wu, Y., Boonplueang, R., Chen, S., Stevenson, F. F., Yantiri, F., Yang, L., Beal, M. F., & Andersen, J. K. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-24-09519.2001 · Cited by 315 · see citing works
Complex I deficiency primes Bax-dependent neuronal apoptosis through mitochondrial oxidative damage
Perier, C., Tieu, K., Guégan, C., Caspersen, C. S., Jackson-Lewis, V. R., Carelli, V., Martinuzzi, A., Hirano, M., Przedborski, S., & Vila, M. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0508215102 · Cited by 308 · see citing works
Self-citationMitochondrial Biology and Parkinson's DiseasePreprint
Perier, C., & Vila, M. (2011) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a009332 · Cited by 304 · see citing works
Self-citationCuervo, A. M., Dice, J. F., & Knecht, E. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.9.5606 · Cited by 299 · see citing works
Deficiency of ATP13A2 Leads to Lysosomal Dysfunction, α-Synuclein Accumulation, and Neurotoxicity
Usenovic, M., Tresse, E., Mazzulli, J. R., Taylor, J. P., & Krainc, D. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.5575-11.2012 · Cited by 291 · see citing works
Offen, D., Beart, P. M., Cheung, N. S., Pascoe, C. J., Hochman, A., Gorodin, S., Melamed, E., Bernard, R., & Bernard, O. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.10.5789 · Cited by 229 · see citing works
Perier, C., Bové, J., Wu, D., Dehay, B., Choi, D., Jackson-Lewis, V. R., Rathke‐Hartlieb, S., Bouillet, P., Strasser, A., Schulz, J. B., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0609874104 · Cited by 229 · see citing works
Self-citationLysosomal destabilization in p53-induced apoptosis
Yuan, X., Li, W., Dalen, H., Lotem, J., Kama, R., Sachs, L., & Brunk, U. T. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.092135599 · Cited by 226 · see citing works
Lysosomal Function and Dysfunction: Mechanism and Disease
Boya, P. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2011.4405 · Cited by 211 · see citing works
Boosting chaperone-mediated autophagy in vivo mitigates α-synuclein-induced neurodegeneration
Xilouri, M., Brekk, O. R., Landeck, N., Pitychoutis, P. M., Papasilekas, T., Papadopoulou-Daifoti, Z., Kirik, D., & Stefanis, L. (2013) · Brain · doi:10.1093/brain/awt131 · Cited by 207 · see citing works
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyride Neurotoxicity Is Attenuated in Mice Overexpressing Bcl-2
Yang, L., Matthews, R. T., Schulz, J. B., Klockgether, T., Liao, A., Martinou, J., Penney, J. B., Hyman, B. T., & Beal, M. F. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-20-08145.1998 · Cited by 199 · see citing works
Oberle, C., Huai, J., Reinheckel, T., Tacke, M., Rassner, M., Ekert, P. G., Buellesbach, J., & Borner, C. (2010) · Cell Death & Differentiation · doi:10.1038/cdd.2009.214 · Cited by 193 · see citing works
Tumor necrosis factor-α-associated lysosomal permeabilization is cathepsin B dependent
Werneburg, N. W., Guicciardi, M. E., Bronk, S. F., & Gores, G. J. (2002) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00151.2002 · Cited by 179 · see citing works
Hetz, C., Vitte, P.-A., Bombrun, A., Rostovtseva, T. K., Montessuit, S., Hiver, A., Schwarz, M. K., Church, D. J., Korsmeyer, S. J., Martinou, J.-C., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m505843200 · Cited by 176 · see citing works
Self-citationBax inhibition protects against free fatty acid-induced lysosomal permeabilization
Feldstein, A. E., Werneburg, N. W., Li, Z., Bronk, S. F., & Gores, G. J. (2006) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00509.2005 · Cited by 174 · see citing works
Mitochondria and Programmed Cell Death in Parkinson's Disease: Apoptosis and Beyond
Perier, C., Bové, J., & Vila, M. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2011.4074 · Cited by 159 · see citing works
Self-citationIs Bax a mitochondrial mediator in apoptotic death of dopaminergic neurons in Parkinson's disease?
Hartmann, A., Michel, P. P., Troadec, J., Prigent, A., Faucheux, B. A., Ruberg, M., Agid, Y., & Hirsch, É. C. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.00160.x · Cited by 153 · see citing works
Werneburg, N. W., Guicciardi, M. E., Bronk, S. F., Kaufmann, S. H., & Gores, G. J. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m705671200 · Cited by 126 · see citing works
Lysosomal membrane permeabilization during apoptosis ‐ involvement of Bax?
Kågedal, K., Johansson, A., Johansson, U., Heimlich, G., Roberg, K. B., Wang, N. S., Jürgensmeier, J. M., & Öllinger, K. M. (2005) · International Journal of Experimental Pathology · doi:10.1111/j.0959-9673.2005.00442.x · Cited by 124 · see citing works
Ramonet, D., Perier, C., Recasens, A., Dehay, B., Bové, J., Costa, V., Scorrano, L., & Vila, M. (2012) · Cell Death and Differentiation · doi:10.1038/cdd.2012.95 · Cited by 104 · see citing works
Self-citationLysosomal membrane permeabilization in Parkinson disease
Vila, M., Bové, J., Dehay, B., Rodríguez‐Muela, N., & Boya, P. (2010) · Autophagy · doi:10.4161/auto.7.1.13933 · Cited by 71 · see citing works
Self-citationApoptosis‐inducing factor deficiency sensitizes dopaminergic neurons to parkinsonian neurotoxins
Perier, C., Bové, J., Dehay, B., Jackson-Lewis, V. R., Rabinovitch, P. S., Przedborski, S., & Vila, M. (2010) · Annals of Neurology · doi:10.1002/ana.22034 · Cited by 58 · see citing works
Self-citationMAC inhibitors suppress mitochondrial apoptosis
Peixoto, P. M. V., Ryu, S.-Y., Bombrun, A., Antonsson, B. E., & Kinnally, K. W. (2009) · Biochemical Journal · doi:10.1042/bj20090664 · Cited by 51 · see citing works
Self-citationMembrane‐permeable Bcl‐xL prevents MPTP‐induced dopaminergic neuronal loss in the substantia nigra
Dietz, G. P. H., von Stockhausen, K., Dietz, B., et al. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.05028.x · Cited by 24 · see citing works
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Gómez-Sintes, R., Ledesma, M. D., & Boya, P. (2016) · Ageing Research Reviews · doi:10.1016/j.arr.2016.02.009 · Cited by 216 · see citing works
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- Authors
- Bové, J., Martínez-Vicente, M., Dehay, B., Perier, C., Recasens, A., Bombrun, A., Antonsson, B., & Vila, M.
- Affiliations
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- Merck Serono S.A. (Switzerland) (CH)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Corresponding author
- Vila, Miquel
- Venue
- Autophagy
- Publisher
- Informa UK Limited
- Published
- 2014-03-26
- Volume
- 10
- Issue
- 5
- Pages
- 889-900
- ISSN
- 1554-8627 (ISSN-L)
- 1554-8635
- PMC
- PMC5119069
- OpenAlex
- W1978412530
- Cited by
- 89
- References
- 42
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 3 · 2023: 4 · 2022: 11 · 2021: 10 · 2020: 10 · 2019: 7 · 2018: 9 · 2017: 10 · 2016: 6 · 2015: 7 · 2014: 2
- FWCI
- 5.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Autophagy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- HAL (submittedVersion)
- Figshare (cc-by)
- Funders
- European Commission
- Instituto de Salud Carlos III
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- Parkinson's disease, Bax, lysosomal membrane permeabilization, lysosomal disruption, autophagosome accumulation, MPTP, mitochondrial membrane permeabilization, dopaminergic neuron loss, Bcl-2 family proteins, nigrostriatal degeneration
- MeSH terms
- Animals, Brain, Cells, Cultured, Humans, Intracellular Membranes, Ion Channels, Lysosomes, Male, Mice, Inbred C57BL, Parkinson Disease, Permeability, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Protein Transport, bcl-2-Associated X Protein, Mice
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