Assembly of α-synuclein and neurodegeneration in the central nervous system of heterozygous M83 mice following the peripheral administration of α-synuclein seeds.
Macdonald, Jennifer A
Chen, John L
Holton, Janice L
Acta Neuropathol Commun
Springer Science and Business Media LLC
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Macdonald, J. A., Chen, J. L., Masuda-Suzukake, M., Schweighauser, M., Jaunmuktane, Z., Warner, T., Holton, J. L., et al. (2021). Assembly of α-synuclein and neurodegeneration in the central nervous system of heterozygous M83 mice following the peripheral administration of α-synuclein seeds.. Acta Neuropathol Commun, 9 (1) https://doi.org/10.1186/s40478-021-01291-7
Peripheral administration (oral, intranasal, intraperitoneal, intravenous) of assembled A53T α-synuclein induced synucleinopathy in heterozygous mice transgenic for human mutant A53T α-synuclein (line M83). The same was the case when cerebellar extracts from a case of multiple system atrophy with type II α-synuclein filaments were administered intraperitoneally, intravenously or intramuscularly. We observed abundant immunoreactivity for pS129 α-synuclein in nerve cells and severe motor impairment, resulting in hindlimb paralysis and shortened lifespan. Filaments immunoreactive for pS129 α-synuclein were in evidence. A 70% loss of motor neurons was present five months after an intraperitoneal injection of assembled A53T α-synuclein or cerebellar extract with type II α-synuclein filaments from an individual with a neuropathologically confirmed diagnosis of multiple system atrophy. Microglial cells changed from a predominantly ramified to a dystrophic appearance. Taken together, these findings establish a close relationship between the formation of α-synuclein inclusions in nerve cells and neurodegeneration, accompanied by a shift in microglial cell morphology. Propagation of α-synuclein inclusions depended on the characteristics of both seeds and transgenically expressed protein.
Research, α-Synuclein, Multiple system atrophy, Seeded assembly, Neurodegeneration, Microglia
UK Medical Research Council (MC_U105184291)
External DOI: https://doi.org/10.1186/s40478-021-01291-7
This record's URL: https://www.repository.cam.ac.uk/handle/1810/331029