Targeted overexpression of human α-synuclein in oligodendroglia induces lesions linked to MSA -like progressive autonomic failure
Open accessAbstract
Multiple system atrophy (MSA) is a rare neurodegenerative disease of undetermined cause manifesting with progressive autonomic failure (AF), cerebellar ataxia and parkinsonism due to neuronal loss in multiple brain areas associated with (oligodendro)glial cytoplasmic alpha-synuclein (alpha SYN) inclusions (GCIs). Using proteolipid protein (PLP)-alpha-synuclein (alpha SYN) transgenic mice we have previously reported parkinsonian motor deficits triggered by MSA-like alpha SYN inclusions. We now extend these observations by demonstrating degeneration of brain areas that are closely linked to progressive AF and other non-motor symptoms in MSA, in (PLP)-alpha SYN transgenic mice as compared to age-matched non-transgenic controls. We show delayed loss of cholinergic neurons in nucleus ambiguus at 12 months of age as well as early neuronal loss in laterodorsal tegmental nucleus, pedunculopontine tegmental nucleus and Onuf's nucleus at 2 months of age associated with alpha SYN oligodendroglial overexpression. We also report that neuronal loss triggered by MSA-like alpha SYN inclusions is absent up to 12 months of age in the thoracic intermediolateral cell column suggesting a differential dynamic modulation of alpha SYN toxicity within the murine autonomic nervous system. Although the spatial and temporal evolution of central autonomic pathology in MSA is unknown our findings corroborate the utility of the (PLP)-alpha SYN transgenic mouse model as a testbed for the study of oligodendroglial alpha SYN mediated neurodegeneration replicating both motor and non-motor aspects of MSA.
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?
Activated microglia are found within white matter tracts and areas of neurodegeneration in patients with MSA, and are believed to release proinflammatory cytokines and possibly play a role in neurodegeneration.
“It has been reported that activated microglia are found within white matter tracts and areas of neurodegeneration in patients with MSA, and are believed to release proinflammatory cytokines and possibly play a role in neurodegeneration [26, 53].”
From Novel oligodendroglial alpha synuclein viral vector models of multiple system atrophy: studies in rodents and nonhuman primates (2017) · cites this paper as [53]
The Discussion (page unavailable) lists microglial activation in an MSA mouse model and suggests a relationship between neuroinflammation and degeneration. It does not report activated microglia in the white matter tracts or degenerating areas of patients with MSA, or say that they release proinflammatory cytokines. (LLM, conf=0.83)
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
The Mouse Brain in Stereotaxic Coordinates
Paxinos, G. (2001) · Cited by 12,859 · see citing works
mouse brain in stereotaxic coordinates
Franklin, K. B. J., & Paxinos, G. (1997) · Cited by 3,258 · see citing works
Second consensus statement on the diagnosis of multiple system atrophy
Gilman, S., Wenning, G. K., Low, P. A., Brooks, D. J., Mathias, C. J., Trojanowski, J. Q., Wood, N. W., Colosimo, C., Dürr, A., Fowler, C. J., et al. (2008) · Neurology · doi:10.1212/01.wnl.0000324625.00404.15 · Cited by 3,140 · see citing works
Self-citationWest, M. J., Slomianka, L., & Gundersen, H. J. G. (1991) · The Anatomical Record · doi:10.1002/ar.1092310411 · Cited by 2,994 · 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
Self-citationA Neurological Syndrome Associated with Orthostatic Hypotension: A Clinical-Pathologic Study
SHY, G. M. (1960) · A.M.A. Archives of Neurology · doi:10.1001/archneur.1960.03840110025004 · Cited by 743 · see citing works
Papp, M. I., & Lantos, P. L. (1994) · Brain · doi:10.1093/brain/117.2.235 · Cited by 389 · see citing works
Multiple system atrophy: an update
Stefanova, N., Bücke, P., Duerr, S., & Wenning, G. K. (2009) · The Lancet Neurology · doi:10.1016/s1474-4422(09)70288-1 · Cited by 374 · see citing works
Self-citationNeuropathological spectrum of synucleinopathies
Jellinger, K. A. (2003) · Movement Disorders · doi:10.1002/mds.10557 · Cited by 338 · see citing works
Wolstenholme, G. E. W., & Freeman, J. S. (1953) · J. & A. Churchill eBooks · Cited by 329 · 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
SNCA variants are associated with increased risk for multiple system atrophy
Scholz, S. W., Houlden, H., Schulte, C., Sharma, M., Li, A., Berg, D., Melchers, A., Paudel, R., Gibbs, J. R., Simón‐Sánchez, J., et al. (2009) · Annals of Neurology · doi:10.1002/ana.21685 · Cited by 280 · see citing works
Self-citationShults, C. W., Rockenstein, E., Crews, L., Adame, A., Mante, M., Larrea, G., Hashimoto, M., Song, D., Iwatsubo, T., Tsuboi, K., et al. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.3527-05.2005 · Cited by 254 · see citing works
Kahle, P. J., Neumann, M., Ozmen, L., Müller, V., Odoy, S., Okamoto, N., Jacobsen, H., Iwatsubo, T., Trojanowski, J. Q., Takahashi, H., et al. (2001) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63072-6 · Cited by 239 · see citing works
Stefanova, N., Reindl, M., Neumann, M., Kahle, P. J., Poewe, W. H., & Wenning, G. K. (2007) · Movement Disorders · doi:10.1002/mds.21671 · Cited by 217 · see citing works
Self-citationThe Spinal Cord: A Christopher and Dana Reeve Foundation Text and Atlas
Anderson, C. R., Ashwell, K. W., Collewijn, H., et al. (2009) · Elsevier eBooks · doi:10.1016/b978-0-12-374247-6.50001-8 · Cited by 213 · 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
Self-citationGenetic Variants of the α-Synuclein Gene SNCA Are Associated with Multiple System Atrophy
Al‐Chalabi, A., Dürr, A., Wood, N. W., Parkinson, M. H., Camuzat, A., Hulot, J., Morrison, K. E., Renton, A. E., Sussmuth, S. D., Landwehrmeyer, G. B., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0007114 · Cited by 197 · see citing works
Multiple system atrophy: α‐synuclein and neuronal degeneration
Yoshida, M. (2007) · Neuropathology · doi:10.1111/j.1440-1789.2007.00841.x · Cited by 184 · see citing works
Lipp, A., Sandroni, P., Ahlskog, J. E., Fealey, R. D., Kimpinski, K., Iodice, V., Gehrking, T. L., Weigand, S. D., Sletten, D. M., Gehrking, J. A., et al. (2009) · Archives of Neurology · doi:10.1001/archneurol.2009.71 · Cited by 154 · see citing works
Self-citationInvolvement of vagal autonomic nuclei in multiple system atrophy and Lewy body disease
Benarroch, E. E., Schmeichel, A. M., Sandroni, P., Low, P. A., & Parisi, J. E. (2006) · Neurology · doi:10.1212/01.wnl.0000196638.98781.bb · Cited by 146 · see citing works
Zuscik, M. J., Sands, S., Ross, S. A., Waugh, D. J. J., Gaivin, R. J., Morilak, D. A., & Perez, D. M. (2000) · Nature Medicine · doi:10.1038/82207 · Cited by 130 · see citing works
Lateral horn cells in progressive autonomic failure
Oppenheimer, D. R. (1980) · Journal of the Neurological Sciences · doi:10.1016/0022-510x(80)90064-7 · Cited by 122 · see citing works
Mesopontine cholinergic neuron involvement in Lewy body dementia and multiple system atrophy
Schmeichel, A. M., Buchhalter, L. C., Low, P. A., Parisi, J. E., Boeve, B. F., Sandroni, P., & Benarroch, E. E. (2008) · Neurology · doi:10.1212/01.wnl.0000298691.71637.96 · Cited by 121 · see citing works
Zuscik, M. J., Chalothorn, D., Hellard, D. T., et al. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m008693200 · Cited by 101 · see citing works
Zhang, B., Veasey, S. C., Wood, M. A., Leng, L. Z., Kaminski, C., Leight, S., Abel, T. G., Lee, V. M. ‐., & Trojanowski, J. Q. (2005) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)61223-0 · Cited by 95 · see citing works
Brainstem in Multiple System Atrophy: Clinicopathological Correlations
Benarroch, E. E. (2003) · Cellular and Molecular Neurobiology · doi:10.1023/a:1025067912199 · Cited by 93 · see citing works
Animal models of multiple system atrophy
Stefanova, N., & Wenning, G. K. (2015) · Clinical Autonomic Research · doi:10.1007/s10286-014-0266-6 · Cited by 93 · see citing works
Self-citationRecent developments in multiple system atrophy
Wenning, G. K., & Stefanova, N. (2009) · Journal of Neurology · doi:10.1007/s00415-009-5173-8 · Cited by 93 · see citing works
Self-citationRasagiline is neuroprotective in a transgenic model of multiple system atrophy
Stefanova, N., Poewe, W. H., & Wenning, G. K. (2007) · Experimental Neurology · doi:10.1016/j.expneurol.2007.11.022 · Cited by 87 · see citing works
Self-citationDepletion of mesopontine cholinergic and sparing of raphe neurons in multiple system atrophy
Benarroch, E. E., Schmeichel, A. M., & Parisi, J. E. (2002) · Neurology · doi:10.1212/wnl.59.6.944 · Cited by 84 · see citing works
When is Onuf's nucleus involved in multiple system atrophy? A sphincter electromyography study
Yamamoto, T. (2005) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.2004.061036 · Cited by 77 · see citing works
Animal models of multiple system atrophy
Stefanova, N., Tison, F., Reindl, M., Poewe, W. H., & Wenning, G. K. (2005) · Trends in Neurosciences · doi:10.1016/j.tins.2005.07.002 · Cited by 70 · see citing works
Self-citationPathological description of a non-motor variant of multiple system atrophy
Gaig, C., Iranzo, Á., Tolosa, E., Vilaseca, I., Rey, M. J., & Santamaría, J. (2008) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.2008.145276 · Cited by 46 · see citing works
Papay, R. S., Zuscik, M. J., Ross, S. A., et al. (2002) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2002.01170.x · Cited by 44 · see citing works
Jacob, D. A. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.1200-05.2005 · Cited by 41 · see citing works
Köllensperger, M., Stampfer‐Kountchev, M., Seppi, K., Geser, F., Frick, C., Sorbo, F. D., Albanese, A., Gurevich, T., Giladi, N., Djaldetti, R., et al. (2006) · European Journal of Neurology · doi:10.1111/j.1468-1331.2006.01554.x · Cited by 39 · see citing works
Self-citationSeney, M. L., Goldman, B. D., & Forger, N. G. (2006) · Journal of Neurobiology · doi:10.1002/neu.20314 · Cited by 33 · see citing works
Neuropathological findings of Onuf's nucleus and its significance
Mannen, T. (2000) · Neuropathology · doi:10.1046/j.1440-1789.2000.00298.x · Cited by 33 · see citing works
Yan, B., Li, L., Harden, S. W., et al. (2009) · Experimental Neurology · doi:10.1016/j.expneurol.2009.07.006 · Cited by 30 · see citing works
Systemic Overexpression of the α1B‐Adrenergic Receptor in Mice: An Animal Model of Epilepsy
Kunieda, T., Zuscik, M. J., Boongird, A., Perez, D. M., Lüders, H. O., & Najm, I. (2002) · Epilepsia · doi:10.1046/j.1528-1157.2002.13202.x · Cited by 29 · see citing works
Striatal transplantation for multiple system atrophy — Are grafts affected by α-synucleinopathy?
Stefanova, N., Hainzer, M., Stemberger, S., Couillard‐Després, S., Aigner, L., Poewe, W. H., & Wenning, G. K. (2009) · Experimental Neurology · doi:10.1016/j.expneurol.2009.05.016 · Cited by 28 · see citing works
Self-citationPropagation of host disease to grafted neurons: Accumulating evidence
Kordower, J. H., & Brundin, P. (2009) · Experimental Neurology · doi:10.1016/j.expneurol.2009.09.016 · Cited by 25 · see citing works
Lumbar motoneuron fate in a mouse model of amyotrophic lateral sclerosis
Hamson, D. K., Hu, J. H., Krieger, C., et al. (2002) · Neuroreport · doi:10.1097/00001756-200212030-00024 · Cited by 18 · see citing works
Koyama, Y., Imada, N., Kawauchi, A., & Kayama, Y. (1999) · Brain Research · doi:10.1016/s0006-8993(99)01770-9 · Cited by 14 · see citing works
Salas, J. C. T., Iwasaki, H., Jodo, E., Schmidt, M. H., Kawauchi, A., Miki, T., Kayama, Y., Otsuki, M., & Koyama, Y. (2007) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00226.2007 · Cited by 13 · see citing works
Quantitative study of intermediolateral column cell counts in Machado-Joseph disease
Sakajiri, K., Makifuchi, T., Fukuhara, N., et al. (1996) · Journal of the Neurological Sciences · doi:10.1016/s0022-510x(96)00221-3 · Cited by 13 · see citing works
Rasagiline in neurodegeneration
Schapira, A. H. V. (2008) · Experimental Neurology · doi:10.1016/j.expneurol.2008.05.002 · Cited by 9 · see citing works
Kobayashi, K., Fukutani, Y., Hayashi, M., et al. (1998) · Journal of the Neurological Sciences · doi:10.1016/s0022-510x(97)00209-8 · Cited by 8 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Expanding the spectrum of neuronal pathology in multiple system atrophy
Cykowski, M. D., Coon, E. A., Powell, S. Z., Jenkins, S. M., Benarroch, E. E., Low, P. A., Schmeichel, A. M., & Parisi, J. E. (2015) · Brain · doi:10.1093/brain/awv114 · Cited by 241 · see citing works
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
Refolo, V., Bez, F., Polissidis, A., Kuzdas-Wood, D., Sturm, E., Kamaratou, M., Poewe, W., Stefanis, L., Angela Cenci, M., Romero-Ramos, M., et al. (2018) · Acta Neuropathologica Communications · doi:10.1186/s40478-017-0504-y · Cited by 67 · see citing works
Self-citationMandel, 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
- Authors
- Stemberger, S., Poewe, W., Wenning, G. K., & Stefanova, N.
- Affiliations
- Innsbruck Medical University (AT)
- Corresponding author
- Wenning, Gregor K.
- Venue
- Experimental Neurology
- Publisher
- Elsevier BV
- Published
- 2010-08
- Volume
- 224
- Issue
- 2
- Pages
- 459-464
- ISSN
- 0014-4886 (ISSN-L)
- PMC
- PMC2913120
- OpenAlex
- W1973365424
- Cited by
- 83
- References
- 50
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 7 · 2022: 2 · 2021: 3 · 2020: 8 · 2019: 1 · 2018: 8 · 2017: 4 · 2016: 7 · 2015: 9 · 2014: 4 · 2013: 8 · 2012: 5
- FWCI
- 4.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Experimental Neurology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Tyrolian Research Funds (TWF UNI-0404/325)
- Austrian Research Foundation (FWF P-19989-B05, DK-C34-B05)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- multiple system atrophy, alpha-synuclein, oligodendroglial inclusions, cholinergic neuron loss, nucleus ambiguus, laterodorsal tegmental nucleus, pedunculopontine nucleus, Onuf's nucleus, intermediolateral cell column, transgenic mouse model, proteolipid protein, neurodegeneration, autonomic nervous system
- MeSH terms
- Animals, Brain, Cell Count, Disease Models, Animal, Humans, Mice, Transgenic, Neurons, Oligodendroglia, Multiple System Atrophy, Mice, alpha-Synuclein
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
