Mouse Model of Multiple System Atrophy α-Synuclein Expression in Oligodendrocytes Causes Glial and Neuronal Degeneration
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Transgenic (Tg) mice overexpressing human wild-type alpha-synuclein in oligodendrocytes under the control of the 2,' 3'-cyclic nucleotide 3'-phosphodiesterase (CNP) promoter are shown here to recapitulate features of multiple system atrophy (MSA), including the accumulation of filamentous human alpha-synuclein aggregates in oligodendrocytes linked to their degeneration and autophagocytosis of myelin. Significantly, endogenous mouse alpha-synuclein also accumulated in normal and degenerating axons and axon terminals in association with oligodendroglia and neuron loss and slowly progressive motor impairments. Our studies demonstrate that overexpression of alpha-synuclein in oligodendrocytes of mice results in MSA-like degeneration in the CNS and that alpha-synuclein inclusions in oligodendrocytes participate in the degeneration of neurons in MSA.
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Transgenic mouse models overexpressing human α-syn under oligodendroglia-specific promoters such as PLP, MBP, and CNP have been developed to study MSA.
“Transgenic (tg) mouse models overexpressing human α-syn under different oligodendroglia-specific promoters, such as proteolipid protein (PLP) [31], myelin basic protein (MBP) [51], and 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNP) [67], have been developed to study MSA.”
From Novel oligodendroglial alpha synuclein viral vector models of multiple system atrophy: studies in rodents and nonhuman primates (2017) · cites this paper as [67]
Mice utilizing CNP-driven overexpression displayed progressive motor impairments and neurodegeneration localized in the spinal cord, with no observed loss in the cerebellum.
“Mice utilizing CNP-driven overexpression displayed progressive motor impairments and neurodegeneration localized in the spinal cord, with no observed loss in the cerebellum [67].”
From Novel oligodendroglial alpha synuclein viral vector models of multiple system atrophy: studies in rodents and nonhuman primates (2017) · cites this paper as [67]
Currently available animal models of MSA are limited to 3 transgenic mouse lines overexpressing human α-syn under PLP, MBP, and CNP promoters.
“Currently available animal models of MSA are limited to 3 tg mouse lines overexpressing human α-syn under proteolipid protein (PLP) promoter [31], myelin basic protein (MBP) promoter [51], and 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNP) promoter [67].”
From Novel oligodendroglial alpha synuclein viral vector models of multiple system atrophy: studies in rodents and nonhuman primates (2017) · cites this paper as [67]
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- Authors
- Yazawa, I., Giasson, B. I., Sasaki, R., Zhang, B., Joyce, S., Uryu, K., Trojanowski, J. Q., & Lee, V. M.-Y.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Lee, Virginia M.-Y.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2005-03
- Volume
- 45
- Issue
- 6
- Pages
- 847-859
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W1980110509
- Cited by
- 301
- References
- 47
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 12 · 2023: 6 · 2022: 7 · 2021: 17 · 2020: 13 · 2019: 19 · 2018: 13 · 2017: 16 · 2016: 9 · 2015: 11 · 2014: 21 · 2013: 22 · 2012: 9
- FWCI
- 11.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 3060 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- National Institutes of Health (AG-09215, NS-044233)
- Naito Foundation
- Okinaka Memorial Institute for Medical Research
- 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, oligodendrocytes, transgenic mouse model, oligodendrocyte degeneration, neurodegeneration, motor impairment, glial degeneration
- MeSH terms
- Animals, Axons, Inclusion Bodies, Central Nervous System, Disease Models, Animal, Humans, Mice, Transgenic, Myelin Sheath, Nerve Tissue Proteins, Neuroglia, Neurons, Oligodendroglia, Phagocytosis, Phosphoric Diester Hydrolases, Promoter Regions, Genetic, Wallerian Degeneration, Presynaptic Terminals, Multiple System Atrophy, Microscopy, Electron, Transmission, Mice, Synucleins, alpha-Synuclein, 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase
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