Altered lipid levels provide evidence for myelin dysfunction in multiple system atrophy
Open accessAbstract
Multiple system atrophy (MSA) is a rapidly-progressive neurodegenerative disease characterized by parkinsonism, cerebellar ataxia and autonomic failure. A pathological hallmark of MSA is the presence of α-synuclein deposits in oligodendrocytes, the myelin-producing support cells of the brain. Brain pathology and in vitro studies indicate that myelin instability may be an early event in the pathogenesis of MSA. Lipid is a major constituent (78% w/w) of myelin and has been implicated in myelin dysfunction in MSA. However, changes, if any, in lipid level/distribution in MSA brain are unknown. Here, we undertook a comprehensive analysis of MSA myelin. We quantitatively measured three groups of lipids, sphingomyelin, sulfatide and galactosylceramide, which are all important in myelin integrity and function, in affected (under the motor cortex) and unaffected (under the visual cortex) white matter regions. For all three groups of lipids, most of the species were severely decreased (40-69%) in affected but not unaffected MSA white matter. An analysis of the distribution of lipid species showed no significant shift in fatty acid chain length/content with MSA. The decrease in lipid levels was concomitant with increased α-synuclein expression. These data indicate that the absolute levels, and not distribution, of myelin lipids are altered in MSA, and provide evidence for myelin lipid dysfunction in MSA pathology. We propose that dysregulation of myelin lipids in the course of MSA pathogenesis may trigger myelin instability.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Alterations in lipid composition are restricted to affected regions in human MSA samples.
“Additionally, alterations in lipid composition are restricted to affected regions in human MSA samples [12].”
From Novel oligodendroglial alpha synuclein viral vector models of multiple system atrophy: studies in rodents and nonhuman primates (2017) · cites this paper as [12]
The Results sections on galactosylceramide and sphingomyelin (page not provided) report reduced lipid levels in MSA-affected motor-cortex white matter but not in the unaffected visual-cortex region examined. The paper distinguishes those changes in absolute levels from lipid-species distribution, which did not significantly change; it also did not test every brain region. Thus the regional finding is supported, but a change in lipid composition or restriction to all affected regions is broader than the findings establish. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Biology of Oligodendrocyte and Myelin in the Mammalian Central Nervous System
Baumann, N., & Pham-Dinh, D. (2001) · Physiological Reviews · doi:10.1152/physrev.2001.81.2.871 · Cited by 1,828 · see citing works
Multiple Sclerosis: An Immune or Neurodegenerative Disorder?
Trapp, B. D., & Nave, K.-A. (2008) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.30.051606.094313 · Cited by 1,724 · see citing works
Axonal damage in acute multiple sclerosis lesions
Ferguson, B. (1997) · Brain · doi:10.1093/brain/120.3.393 · Cited by 1,532 · see citing works
An Overview of Sphingolipid Metabolism: From Synthesis to Breakdown
Gault, C. R., Obeid, L. M., & Hannun, Y. A. (2010) · Advances in experimental medicine and biology · doi:10.1007/978-1-4419-6741-1_1 · Cited by 1,078 · see citing works
Papp, M. I., Kahn, J. E., & Lantos, P. L. (1989) · Journal of the Neurological Sciences · doi:10.1016/0022-510x(89)90219-0 · Cited by 991 · 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
Lipid composition of the normal human brain: gray matter, white matter, and myelin
O'Brien, J. S., & Sampson, E. L. (1965) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)39619-x · Cited by 848 · see citing works
Multiple system atrophy: A review of 203 pathologically proven cases
Wenning, G. K., Tison, F., Ben‐Shlomo, Y., Daniel, S. E., & Quinn, N. P. (1997) · Movement Disorders · doi:10.1002/mds.870120203 · Cited by 802 · see citing works
Benes, F. M. (1994) · Archives of General Psychiatry · doi:10.1001/archpsyc.1994.03950060041004 · Cited by 744 · see citing works
Prolonged myelination in human neocortical evolution
Miller, D. J., Duka, T., Stimpson, C. D., Schapiro, S. J., Baze, W. B., McArthur, M. J., Fobbs, A. J., Sousa, A. M. M., Šestan, N., Wildman, D. E., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1117943109 · Cited by 699 · see citing works
Prevalence of progressive supranuclear palsy and multiple system atrophy: a cross-sectional study
Schrag, A. E., Ben‐Shlomo, Y., & Quinn, N. P. (1999) · The Lancet · doi:10.1016/s0140-6736(99)04137-9 · Cited by 640 · see citing works
Scheiffele, P., Roth, M. G., & Simons, K. (1997) · The EMBO Journal · doi:10.1093/emboj/16.18.5501 · Cited by 638 · see citing works
Coetzee, T., Fujita, N., Dupree, J. L., Shi, R., Blight, A. R., Suzuki, K., Suzuki, K., & Popko, B. (1996) · Cell · doi:10.1016/s0092-8674(00)80093-8 · Cited by 624 · see citing works
Development and validation of the Unified Multiple System Atrophy Rating Scale (UMSARS)
Wenning, G. K., Tison, F., Seppi, K., Sampaio, C., Diem, A., Yekhlef, F., Ghorayeb, I., Ory‐Magne, F., Galitzky, M., Scaravilli, T., et al. (2004) · Movement Disorders · doi:10.1002/mds.20255 · Cited by 606 · see citing works
Bielawski, J., Szulc, Z. M., Hannun, Y. A., & Bielawska, A. E. (2006) · Methods · doi:10.1016/j.ymeth.2006.05.004 · Cited by 543 · see citing works
When Do Lasses (Longevity Assurance Genes) Become CerS (Ceramide Synthases)?
Pewzner-Jung, Y., Ben-Dor, S., & Futerman, A. H. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.r600010200 · Cited by 435 · see citing works
Structure-Function Analysis of Bcl-2 Protein
Hanada, M., Aimé, C., Sato, T., & Reed, J. C. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.20.11962 · Cited by 419 · see citing works
Bower, J. H., Maraganore, D. M., McDonnell, S. K., et al. (1997) · Neurology · doi:10.1212/wnl.49.5.1284 · Cited by 400 · see citing works
Mammalian Lass6 and its related family members regulate synthesis of specific ceramides
Mizutani, Y., Kihara, A., & Igarashi, Y. (2005) · Biochemical Journal · doi:10.1042/bj20050291 · Cited by 376 · see citing works
Bosio, A., Binczek, E., & Stoffel, W. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.23.13280 · Cited by 347 · see citing works
Clearance and deposition of extracellular α-synuclein aggregates in microglia
Lee, H.-J., Suk, J.-E., Bae, E.-J., & Lee, S.-J. (2008) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2008.05.045 · Cited by 343 · see citing works
Wilkins, A., Majed, H., Layfield, R., Compston, A., & Chandran, S. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-12-04967.2003 · Cited by 337 · see citing works
Hyperphosphorylation and insolubility of α‐synuclein in transgenic mouse oligodendrocytes
Kahle, P. J., Neumann, M., Ozmen, L., Müller, V., Jacobsen, H., Spooren, W., Fuss, B., Mallon, B., Macklin, W. B., Fujiwara, H., et al. (2002) · The EMBO Reports · doi:10.1093/embo-reports/kvf109 · Cited by 314 · see citing works
Yazawa, I., Giasson, B. I., Sasaki, R., Zhang, B., Joyce, S., Uryu, K., Trojanowski, J. Q., & Lee, V. M.-Y. (2005) · Neuron · doi:10.1016/j.neuron.2005.01.032 · Cited by 301 · see citing works
Imgrund, S., Hartmann, D., Farwanah, H., Eckhardt, M., Sandhoff, R., Degen, J., Gieselmann, V., Sandhoff, K., & Willecke, K. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.031971 · Cited by 299 · see citing works
Riebeling, C., Allegood, J. C., Wang, E. L., Merrill, A. H., & Futerman, A. H. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m307104200 · Cited by 292 · see citing works
Venkataraman, K., Riebeling, C., Bodennec, J., Riezman, H., Allegood, J. C., Sullards, M. C., Merrill, A. H., & Futerman, A. H. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m205211200 · Cited by 282 · see citing works
C26‐CoA‐dependent ceramide synthesis of Saccharomyces cerevisiae is operated by Lag1p and Lac1p
Guillas, I., Kirchman, P. A., Chuard, R., Pfefferli, M., Jiang, J. C., Jazwinski, S. M., & Conzelmann, A. (2001) · The EMBO Journal · doi:10.1093/emboj/20.11.2655 · Cited by 277 · see citing works
Sulfatide is essential for the maintenance of CNS myelin and axon structure
Marcus, J., Honigbaum, S., Shroff, S., Honke, K., D, J. R. M., & Dupree, J. L. (2005) · Glia · doi:10.1002/glia.20292 · Cited by 250 · see citing works
Campbell, B. C. V., McLean, C., Culvenor, J. G., Gai, W., Blumbergs, P. C., Jäkälä, P., Beyreuther, K. T., Masters, C. L., & Li, Q. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.00021.x · Cited by 221 · 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
Hanada, K., Nishijima, M., Akamatsu, Y., & Pagano, R. E. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.11.6254 · Cited by 203 · see citing works
p25α Relocalizes in Oligodendroglia from Myelin to Cytoplasmic Inclusions in Multiple System Atrophy
Song, Y. J. C., Lundvig, D. M. S., Huang, Y. M., Gai, W., Blumbergs, P. C., Højrup, P., Otzen, D. E., Halliday, G. M., & Jensen, P. H. (2007) · American Journal Of Pathology · doi:10.2353/ajpath.2007.070201 · Cited by 201 · see citing works
Self-citationAbsence of α-synuclein mRNA expression in normal and multiple system atrophy oligodendroglia
Miller, D. W., Johnson, J. M., Solano, S. M., Hollingsworth, Z. R., Standaert, D. G., & Young, A. B. (2005) · Journal of Neural Transmission · doi:10.1007/s00702-005-0378-1 · Cited by 198 · see citing works
Mizutani, Y., Kihara, A., & Igarashi, Y. (2006) · Biochemical Journal · doi:10.1042/bj20060379 · Cited by 179 · see citing works
Non-Aβ Component of Alzheimer's Disease Amyloid (NAC) Revisited
Culvenor, J. G., McLean, C., Cutt, S., Campbell, B. C. V., Maher, F., Jäkälä, P., Hartmann, T., Beyreuther, K. T., Masters, C. L., & Li, Q. (1999) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)65220-0 · Cited by 176 · see citing works
Mass Spectrometric Identification of Increased C16 Ceramide Levels During Apoptosis
Thomas, R. L., Matsko, C. M., Lotze, M. T., & Amoscato, A. A. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.43.30580 · Cited by 150 · see citing works
Mori, F., Tanji, K., Yoshimoto, M., Takahashi, H., & Wakabayashi, K. (2002) · Experimental Neurology · doi:10.1006/exnr.2002.7929 · Cited by 149 · see citing works
Survival in multiple system atrophy
Schrag, A. E., Wenning, G. K., Quinn, N. P., & Ben‐Shlomo, Y. (2007) · Movement Disorders · doi:10.1002/mds.21839 · Cited by 130 · see citing works
The Role of the Ceramide Acyl Chain Length in Neurodegeneration: Involvement of Ceramide Synthases
Ben‐David, O., & Futerman, A. H. (2010) · NeuroMolecular Medicine · doi:10.1007/s12017-010-8114-x · Cited by 130 · see citing works
LASS5 Is a Bona Fide Dihydroceramide Synthase That Selectively Utilizes Palmitoyl-CoA as Acyl Donor
Lahiri, S., & Futerman, A. H. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m506485200 · Cited by 123 · see citing works
Kroesen, B., Jacobs, S. C., Pettus, B. J., Sietsma, H., Kok, J., Hannun, Y. A., & de Leij, L. F. M. H. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m210756200 · Cited by 109 · see citing works
Becker, I., Wang‐Eckhardt, L., Yaghootfam, A., Gieselmann, V., & Eckhardt, M. (2007) · Histochemistry and Cell Biology · doi:10.1007/s00418-007-0344-0 · Cited by 101 · see citing works
Causes of death in multiple system atrophy
Papapetropoulos, S., Tuchman, A., Laufer, D., Papatsoris, A., Papapetropoulos, N., & Mash, D. C. (2006) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.2006.103929 · Cited by 85 · see citing works
Reduced parietal connectivity with a premotor writing area in writer's cramp
Delnooz, C. C. S., Helmich, R. C. G., Toni, I., & van de Warrenburg, B. P. C. (2012) · Movement Disorders · doi:10.1002/mds.25029 · Cited by 79 · see citing works
Ozawa, T. (2007) · Acta Neuropathologica · doi:10.1007/s00401-007-0254-1 · Cited by 77 · see citing works
Bosio, A., Binczek, E., Haupt, W. F., et al. (1998) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1998.70010308.x · Cited by 75 · see citing works
Multiple system atrophy/progressive supranuclear palsy: α-Synuclein, synphilin, tau, and APOE
Morris, H. R., Vaughan, J. R., Datta, S. R., et al. (2000) · Neurology · doi:10.1212/wnl.55.12.1918 · Cited by 73 · see citing works
Ozawa, T., Takano, H., Onodera, O., Kobayashi, H., Ikeuchi, T., Koide, R., Okuizumi, K., Shimohata, T., Wakabayashi, K., Takahashi, H., et al. (1999) · Neuroscience Letters · doi:10.1016/s0304-3940(99)00475-9 · Cited by 61 · see citing works
ABCA8 stimulates sphingomyelin production in oligodendrocytes
Kim, W. S., Hsiao, J.-H. T., Bhatia, S., Glaros, E. N., Don, A. S., Tsuruoka, S., Weickert, C. S., & Halliday, G. M. (2013) · Biochemical Journal · doi:10.1042/bj20121764 · Cited by 52 · see citing works
Self-citationHejazi, L., Wong, J. W. H., Cheng, D., Proschogo, N. W., Ebrahimi, D., Garner, B., & Don, A. S. (2011) · Biochemical Journal · doi:10.1042/bj20110566 · Cited by 49 · see citing works
Self-citationQuantitative PCR-based screening of α-synuclein multiplication in multiple system atrophy
Lincoln, S. J., Ross, O. A., Milkovic, N. M., et al. (2007) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2006.12.005 · Cited by 38 · see citing works
Bleasel, J. M., Hsiao, J.-H. T., Halliday, G. M., & Kim, W. S. (2013) · Journal of Parkinson s Disease · doi:10.3233/jpd-130203 · Cited by 25 · see citing works
Self-citationMMSAT: Automated Quantification of Metabolites in Selected Reaction Monitoring Experiments
Wong, J. W. H., Abuhusain, H. J., McDonald, K. L., et al. (2011) · Analytical Chemistry · doi:10.1021/ac2026578 · Cited by 22 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Oligodendroglia and Myelin in Neurodegenerative Diseases: More Than Just Bystanders?
Ettle, B., Schlachetzki, J. C. M., & Winkler, J. (2016) · Molecular Neurobiology · doi:10.1007/s12035-015-9205-3 · Cited by 160 · see citing works
Lysosomes as Oxidative Targets for Cancer Therapy
Dielschneider, R. F., Henson, E. S., & Gibson, S. B. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/3749157 · Cited by 123 · see citing works
T cell infiltration in both human multiple system atrophy and a novel mouse model of the disease
Williams, G. P., Marmion, D. J., Schonhoff, A. M., Jurkuvenaite, A., Won, W.-J., Standaert, D. G., Kordower, J. H., & Harms, A. S. (2020) · Acta Neuropathologica · doi:10.1007/s00401-020-02126-w · Cited by 102 · see citing works
Mandel, R. J., Marmion, D. J., Kirik, D., Chu, Y., Heindel, C., McCown, T., Gray, S. J., & Kordower, J. H. (2017) · Acta Neuropathologica Communications · doi:10.1186/s40478-017-0451-7 · Cited by 56 · see citing works
Animal modeling an oligodendrogliopathy – multiple system atrophy
Bleasel, J. M., Halliday, G. M., & Kim, W. S. (2016) · Acta Neuropathologica Communications · doi:10.1186/s40478-016-0279-6 · Cited by 19 · see citing works
Self-citation
- Authors
- Don, A. S., Hsiao, J.-H. T., Bleasel, J. M., Couttas, T. A., Halliday, G. M., & Kim, W. S.
- Affiliations
- UNSW Sydney (AU)
- Neuroscience Research Australia (AU)
- Corresponding author
- Kim, Woojin Scott
- ORCID
- Venue
- Acta Neuropathologica Communications
- Published
- 2014-10-29
- Volume
- 2
- Issue
- 1
- Pages
- 150-150
- ISSN
- 2051-5960 (ISSN-L)
- PMC
- PMC4228091
- OpenAlex
- W2165915481
- Cited by
- 88
- References
- 55
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 12 · 2023: 4 · 2022: 6 · 2021: 10 · 2020: 13 · 2019: 7 · 2018: 4 · 2017: 10 · 2016: 7 · 2015: 4
- FWCI
- 4.57
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Acta Neuropathologica Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Neuroscience Research Australia
- University of New South Wales
- University of Sydney
- National Institutes of Health
- Medical Research Council
- National Health and Medical Research Council (1022325, 630434)
- National Institute on Alcohol Abuse and Alcoholism (R24AA012725, NIH (NIAAA) R24AA012725, R28AA012725)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Keywords
- multiple system atrophy, myelin lipids, sphingomyelin, sulfatide, galactosylceramide, alpha-synuclein, oligodendrocytes, white matter, neurodegeneration, fatty acid chain length
- MeSH terms
- Aged, Aged, 80 and over, Brain Chemistry, Female, Galactosylceramides, Glycolipids, Humans, Male, Middle Aged, Myelin Sheath, Sphingomyelins, Sulfoglycosphingolipids, Multiple System Atrophy, alpha-Synuclein, White Matter
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
