Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein.
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.
Pubmed ID: 12062037 RIS Download
Animals | Axons | Behavior, Animal | Brain | Disease Models, Animal | Female | Gene Expression Regulation | Humans | Inclusion Bodies | Male | Mice | Mice, Transgenic | Microscopy, Electron | Movement Disorders | Nerve Tissue Proteins | Neurodegenerative Diseases | Neurons | Phenotype | Recombinant Fusion Proteins | Solubility | Spinal Cord | Synucleins | Wallerian Degeneration | alpha-Synuclein