α-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 α-synuclein lesions lead to neurodegeneration, this remains controversial. To explore this issue, we generated transgenic mice expressing wild-type and A53T human α-synuclein in CNS neurons. Mice expressing mutant, but not wild-type, α-synuclein developed a severe and complex motor impairment leading to paralysis and death. These animals developed age-dependent intracytoplasmic neuronal α-synuclein inclusions paralleling disease onset, and the α-synuclein inclusions recapitulated features of human counterparts. Moreover, immunoelectron microscopy revealed that the α-synuclein inclusions contained 10-16 nm wide fibrils similar to human pathological inclusions. These mice demonstrate that A53T α-synuclein leads to the formation of toxic filamentous α-synuclein neuronal inclusions that cause neurodegeneration.
Giasson, B. I., Duda, J. E., Quinn, S. M., Zhang, B., Trojanowski, J. Q., & Lee, V. M. Y. (2002). Neuronal α-synucleinopathy with severe movement disorder in mice expressing A53T human α-synuclein. Neuron, 34(4), 521–533. https://doi.org/10.1016/S0896-6273(02)00682-7