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      Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein.

      Neuron

      Animals, Axons, metabolism, pathology, ultrastructure, Behavior, Animal, physiology, Brain, Disease Models, Animal, Female, Gene Expression Regulation, Humans, Inclusion Bodies, Male, Mice, Mice, Transgenic, Microscopy, Electron, Movement Disorders, genetics, Nerve Tissue Proteins, Neurodegenerative Diseases, Neurons, Phenotype, Recombinant Fusion Proteins, Solubility, Spinal Cord, Synucleins, Wallerian Degeneration, alpha-Synuclein

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          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.

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          12062037

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