Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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2',3'-Cyclic Nucleotide 3'-Phosphodiesterase
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Animals
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Axons / metabolism
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Axons / pathology
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Axons / ultrastructure
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Central Nervous System / metabolism
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Central Nervous System / pathology
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Central Nervous System / physiopathology
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Disease Models, Animal
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Humans
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Inclusion Bodies / genetics
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Inclusion Bodies / metabolism
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Inclusion Bodies / pathology
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Mice
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Mice, Transgenic
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Microscopy, Electron, Transmission
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Multiple System Atrophy / genetics
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Multiple System Atrophy / metabolism*
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Multiple System Atrophy / physiopathology
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Myelin Sheath / metabolism
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Myelin Sheath / pathology
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Myelin Sheath / ultrastructure
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Neuroglia / pathology*
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Neurons / pathology*
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Oligodendroglia / metabolism*
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Oligodendroglia / pathology
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Oligodendroglia / ultrastructure
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Phagocytosis / genetics
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Phosphoric Diester Hydrolases / genetics
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Presynaptic Terminals / metabolism
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Presynaptic Terminals / pathology
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Presynaptic Terminals / ultrastructure
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Promoter Regions, Genetic / genetics
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Synucleins
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Wallerian Degeneration / genetics
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Wallerian Degeneration / metabolism*
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Wallerian Degeneration / physiopathology
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alpha-Synuclein
Substances
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Nerve Tissue Proteins
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SNCA protein, human
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Snca protein, mouse
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Synucleins
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alpha-Synuclein
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Phosphoric Diester Hydrolases
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2',3'-Cyclic Nucleotide 3'-Phosphodiesterase
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CNP protein, human
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Cnp protein, mouse