Lipidomic Analysis of α-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment
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In Parkinson's disease (PD), α-synuclein (αS) pathologically impacts the brain, a highly lipid-rich organ. We investigated how alterations in αS or lipid/fatty acid homeostasis affect each other. Lipidomic profiling of human αS-expressing yeast revealed increases in oleic acid (OA, 18:1), diglycerides, and triglycerides. These findings were recapitulated in rodent and human neuronal models of αS dyshomeostasis (overexpression; patient-derived triplication or E46K mutation; E46K mice). Preventing lipid droplet formation or augmenting OA increased αS yeast toxicity; suppressing the OA-generating enzyme stearoyl-CoA-desaturase (SCD) was protective. Genetic or pharmacological SCD inhibition ameliorated toxicity in αS-overexpressing rat neurons. In a C. elegans model, SCD knockout prevented αS-induced dopaminergic degeneration. Conversely, we observed detrimental effects of OA on αS homeostasis: in human neural cells, excess OA caused αS inclusion formation, which was reversed by SCD inhibition. Thus, monounsaturated fatty acid metabolism is pivotal for αS-induced neurotoxicity, and inhibiting SCD represents a novel PD therapeutic approach.
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“We also observed sensitivity of oligodendrocytes to changes in lipoapoptosis modulating genes Scd1 and Insig1 (Extended Data Figure 8b-c)16,17.”
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Stearoyl-CoA Desaturase-2 in Murine Development, Metabolism, and Disease
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Tardiff, D. F., Lucas, M. C., Wrona, I. E., Chang, B., Chung, C. Y., Bourdonnec, B. L., Rhodes, K. J., & Scannevin, R. H. (2022) · Molecular Neurobiology · doi:10.1007/s12035-021-02695-1 · Cited by 33 · see citing works
Lipid Homeostasis and Its Links With Protein Misfolding Diseases
Vendruscolo, M. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.829291 · Cited by 33 · see citing works
Lipid Analysis of the 6-Hydroxydopamine-Treated SH-SY5Y Cell Model for Parkinson’s Disease
Xicoy, H., Brouwers, J. F. H. M., Kalnytska, O., Wieringa, B., & Martens, G. J. M. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-01733-3 · Cited by 32 · see citing works
Brzozowski, C. F., Hijaz, B. A., Singh, V., Gcwensa, N. Z., Kelly, K., Boyden, E. S., West, A. B., Sarkar, D., & Volpicelli‐Daley, L. A. (2021) · Acta Neuropathologica Communications · doi:10.1186/s40478-021-01283-7 · Cited by 32 · see citing works
A Brain-Penetrant Stearoyl-CoA Desaturase Inhibitor Reverses α-Synuclein Toxicity
Nuber, S., Chung, C. Y., Tardiff, D. F., Bechade, P. A., McCaffery, T. D., Shimanaka, K., Choi, J., Chang, B., Raja, W. K., Neves, E., et al. (2022) · Neurotherapeutics · doi:10.1007/s13311-022-01199-7 · Cited by 32 · see citing works
Self-citationLipidomics analysis in drug discovery and development.
Kostidis, S., Sánchez-López, E., & Giera, M. (2022) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2022.102256 · Cited by 25 · see citing works
Devkota, R., Kaper, D., Bodhicharla, R. K., Henricsson, M., Borén, J., & Pilon, M. (2021) · Genetics · doi:10.1093/genetics/iyab093 · Cited by 30 · see citing works
Fonseca‐Ornelas, L., Stricker, J. M. S., Soriano-Cruz, S., Weykopf, B., Dettmer, U., Muratore, C., Scherzer, C. R., & Selkoe, D. J. (2022) · npj Parkinson s Disease · doi:10.1038/s41531-022-00380-1 · Cited by 30 · see citing works
Self-citationLipid droplets in the nervous system: involvement in cell metabolic homeostasis
Zhang, Y., Chen, Y., Zhuang, C., Qi, J., Zhao, R. C., & Wang, J. (2024) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-23-01401 · Cited by 30 · see citing works
Beal, M. F., Chiluwal, J., Calingasan, N. Y., Milne, G. L., Shchepinov, M. S., & Tapias, V. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-01090-6 · Cited by 28 · see citing works
Temperature is a key determinant of alpha- and beta-synuclein membrane interactions in neurons
Ramalingam, N., & Dettmer, U. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100271 · Cited by 28 · see citing works
Self-citationNeutral lipids as early biomarkers of cellular fate: the case of α-synuclein overexpression
Alza, N. P., Conde, M. A., Bilbao, P., & Salvador, G. A. (2021) · Cell Death and Disease · doi:10.1038/s41419-020-03254-7 · Cited by 28 · see citing works
- Authors
- Fanning, S., Haque, A., Imberdis, T., Baru, V., Barrasa, M. I., Nuber, S., Termine, D., Ramalingam, N., Ho, G. P. H., Noble, T., Sandoe, J., Lou, Y., Landgraf, D., Freyzon, Y., Newby, G., Soldner, F., Terry-Kantor, E., Kim, T.-E., Hofbauer, H. F., Becuwe, M., Jaenisch, R., Pincus, D., Clish, C. B., Walther, T. C., Farese, R. V., Srinivasan, S., Welte, M. A., Kohlwein, S. D., Dettmer, U., Lindquist, S., & Selkoe, D.
- Affiliations
- Brigham and Women's Hospital (US)
- Whitehead Institute for Biomedical Research (US)
- MiraCosta College (US)
- University of Graz (AT)
- Harvard University (US)
- Broad Institute (US)
- Howard Hughes Medical Institute (US)
- Scripps Research Institute (US)
- University of Rochester (US)
- Corresponding author
- Dettmer, Ulf
- Selkoe, Dennis
- ORCID
- Fanning, Saranna
- Imberdis, Thibaut
- Baru, Valeriya
- Barrasa, M. Inmaculada
- Nuber, Silke
- Ramalingam, Nagendran
- Ho, Gary P.H.
- Landgraf, Dirk
- Newby, Gregory
- Soldner, Frank
- Terry-Kantor, Elizabeth
- Kim, Tae-Eun
- Hofbauer, Harald F.
- Jaenisch, Rudolf
- Pincus, David
- Clish, Clary B.
- Walther, Tobias C.
- Farese, Robert V.
- Welte, Michael A.
- Kohlwein, Sepp D.
- Dettmer, Ulf
- Selkoe, Dennis
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2019-03
- Volume
- 73
- Issue
- 5
- Pages
- 1001-1014.e8
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC6408259
- OpenAlex
- W2902875229
- Cited by
- 285
- References
- 95
- Citations by year
- 2026: 32 · 2025: 40 · 2024: 46 · 2023: 33 · 2022: 35 · 2021: 43 · 2020: 39 · 2019: 17
- FWCI
- 16.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- PMC
- Funders
- Austrian Science Fund FWF
- DK Molecular Enzymology Project (W901)
- NAWI Graz
- JPB Foundation
- HHMI
- Jane Coffin Childs Memorial Fund
- NIH (NS065743, GM102155, NS103123, NS099328, NS083845)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- alpha-synuclein, Parkinson's disease, stearoyl-CoA desaturase, oleic acid, lipidomics, neurotoxicity, lipid droplets, monounsaturated fatty acids, fatty acid metabolism, alpha-synuclein aggregation, dopaminergic neurons, therapeutic target
- MeSH terms
- Animals, Antiparkinson Agents, Cell Line, Cerebral Cortex, Diglycerides, Disease Models, Animal, Enzyme Inhibitors, Humans, Mice, Inbred C57BL, Mice, Transgenic, Nerve Degeneration, Neurons, Parkinson Disease, Saccharomyces cerevisiae, Stearoyl-CoA Desaturase, Triglycerides, Caenorhabditis elegans, Rats, Sprague-Dawley, Oleic Acid, Lipid Metabolism, alpha-Synuclein, Metabolomics, Drug Discovery, Induced Pluripotent Stem Cells, Neural Stem Cells, Molecular Targeted Therapy, Dopaminergic Neurons, Lipid Droplets
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