Abstract
alpha-Synucleinopathies are neurodegenerative disorders that range pathologically from the demise of select groups of nuclei to pervasive degeneration throughout the neuraxis. Although mounting evidence suggests that alpha-synuclein lesions lead to neurodegeneration, this remains controversial. To explore this issue, we generated transgenic mice expressing wild-type and A53T human alpha-synuclein in CNS neurons. Mice expressing mutant, but not wild-type, alpha-synuclein developed a severe and complex motor impairment leading to paralysis and death. These animals developed age-dependent intracytoplasmic neuronal alpha-synuclein inclusions paralleling disease onset, and the alpha-synuclein inclusions recapitulated features of human counterparts. Moreover, immunoelectron microscopy revealed that the alpha-synuclein inclusions contained 10-16 nm wide fibrils similar to human pathological inclusions. These mice demonstrate that A53T alpha-synuclein leads to the formation of toxic filamentous alpha-synuclein neuronal inclusions that cause neurodegeneration.
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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Animals
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Axons / metabolism
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Axons / pathology
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Axons / ultrastructure
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Behavior, Animal / physiology
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Brain / metabolism*
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Brain / pathology
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Brain / ultrastructure
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Disease Models, Animal
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Female
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Gene Expression Regulation / physiology
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Humans
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Inclusion Bodies / metabolism*
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Inclusion Bodies / pathology
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Inclusion Bodies / ultrastructure
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Male
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Mice
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Mice, Transgenic
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Microscopy, Electron
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Movement Disorders / genetics*
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Movement Disorders / metabolism
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Movement Disorders / pathology
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Nerve Tissue Proteins / genetics*
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Nerve Tissue Proteins / metabolism
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Nerve Tissue Proteins / ultrastructure
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Neurodegenerative Diseases / genetics*
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Neurodegenerative Diseases / metabolism
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Neurodegenerative Diseases / pathology
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Neurons / metabolism*
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Neurons / pathology
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Neurons / ultrastructure
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Phenotype
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Recombinant Fusion Proteins / ultrastructure
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Solubility
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Spinal Cord / metabolism*
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Spinal Cord / pathology
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Spinal Cord / ultrastructure
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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 / pathology
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alpha-Synuclein
Substances
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Nerve Tissue Proteins
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Recombinant Fusion 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