Neurological and Neurodegenerative Alterations in a Transgenic Mouse Model Expressing Human α-Synuclein under Oligodendrocyte Promoter: Implications for Multiple System Atrophy
Open accessAbstract
Multiple system atrophy (MSA) is a progressive, neurodegenerative disease characterized by parkinsonism, ataxia, autonomic dysfunction, and accumulation of α-synuclein (α-syn) in oligodendrocytes. To better understand the mechanisms of neurodegeneration and the role of α-syn accumulation in oligodendrocytes in the pathogenesis of MSA, we generated transgenic mouse lines expressing human (h) α-syn under the control of the murine myelin basic protein promoter. Transgenic mice expressing high levels of hα-syn displayed severe neurological alterations and died prematurely at 6 months of age. Furthermore, mice developed progressive accumulation of hα-syn-immunoreactive inclusions in oligodendrocytes along the axonal tracts in the brainstem, basal ganglia, cerebellum, corpus callosum, and neocortex. The inclusions also reacted with antibodies against phospho-serine (129) hα-syn and ubiquitin, and hα-syn was found in the detergent-insoluble fraction. In high-expresser lines, the white matter tracts displayed intense astrogliosis, myelin pallor, and decreased neurofilament immunostaining. Accumulation of hα-syn in oligodendrocytes also leads to prominent neurodegenerative changes in the neocortex with decreased dendritic density and to loss of dopaminergic fibers in the basal ganglia. The oligodendrocytic inclusions were composed of fibrils and accompanied by mitochondrial alterations and disruption of the myelin lamina in the axons. Together, these studies support the contention that accumulation of α-syn in oligodendrocytes promotes neurodegeneration and recapitulates several of the key functional and neuropathological features of MSA.
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Overexpression of α-syn using the MBP promoter showed the most classical distribution of pathology, with both the basal ganglia and cerebellum displaying extensive pathology.
“Overexpression of α-syn using the MBP promoter showed the most classical distribution of pathology, with both the basal ganglia and cerebellum displaying extensive pathology [51].”
From Novel oligodendroglial alpha synuclein viral vector models of multiple system atrophy: studies in rodents and nonhuman primates (2017) · cites this paper as [51]
The Discussion reports extensive α-synuclein accumulation and associated neurodegeneration in the basal ganglia and cerebellum of MBP-promoter mice. It also describes more extensive alterations in these regions than in another model, but does not establish that the MBP model had the *most classical* distribution of pathology. (LLM, conf=0.84)
Experimental — accuracy not yet measuredTransgenic 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 [51]
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 [51]
The degree of GCI accumulation, neurodegeneration, and motor impairments varied significantly with α-syn expression levels, where high expressing lines demonstrated the most significant neuropathological and behavioral deficits.
“The degree of GCI accumulation, neurodegeneration, and motor impairments varied significantly with α-syn expression levels, where high expressing lines demonstrated the most significant neuropathological and behavioral deficits [51].”
From Novel oligodendroglial alpha synuclein viral vector models of multiple system atrophy: studies in rodents and nonhuman primates (2017) · cites this paper as [51]
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References 86 · Cited by 254
- Authors
- Shults, C. W., Rockenstein, E., Crews, L., Adame, A., Mante, M., Larrea, G., Hashimoto, M., Song, D., Iwatsubo, T., Tsuboi, K., & Masliah, E.
- Affiliations
- University of California San Diego (US)
- The University of Tokyo (JP)
- Corresponding author
- Masliah, Eliezer
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2005-11-16
- Volume
- 25
- Issue
- 46
- Pages
- 10689-10699
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6725840
- OpenAlex
- W2153235303
- Cited by
- 254
- References
- 86
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 20 · 2023: 8 · 2022: 7 · 2021: 20 · 2020: 13 · 2019: 13 · 2018: 10 · 2017: 14 · 2016: 7 · 2015: 13 · 2014: 16 · 2013: 21 · 2012: 14
- FWCI
- 4.33
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Michael J. Fox Foundation for Parkinson's Research
- National Institutes of Health (AG5131, AG‐022074, AG‐18440, NS044233)
- National Institute on Aging (R37AG018440, R01AG018440, P50AG005131, AG-5131, AG022074, AG 18440, P01AG022074)
- National Institute of Neurological Disorders and Stroke (P01NS044233)
- 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, myelin basic protein promoter, neurodegeneration, ubiquitin, astrocyte activation, demyelination, neurofilaments, basal ganglia, mitochondrial changes, parkinsonism, ataxia, autonomic dysfunction
- MeSH terms
- Animals, Disease Models, Animal, Humans, Male, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Transgenic, Middle Aged, Nerve Degeneration, Oligodendroglia, Promoter Regions, Genetic, Multiple System Atrophy, Mice, alpha-Synuclein
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