Assembly of [alpha]-synuclein and neurodegeneration in the central nervous system of heterozygous M83 mice following the peripheral administration of [alpha]-synuclein seeds

• Published in: Acta neuropathologica communications Vol. 9; no. 1
• Main Authors: Macdonald, Jennifer A, Chen, John L, Masuda-Suzukake, Masami, Schweighauser, Manuel, Jaunmuktane, Zane, Warner, Thomas, Holton, Janice L, Grossman, Annabelle, Berks, Richard, Lavenir, Isabelle, Goedert, Michel
• Format: Journal Article
• Language: English
• Published: BioMed Central Ltd 24.11.2021
• Subjects: Genetic engineering; Neurons; Seeds
• ISSN: 2051-5960; 2051-5960
• DOI: 10.1186/s40478-021-01291-7

Peripheral administration (oral, intranasal, intraperitoneal, intravenous) of assembled A53T [alpha]-synuclein induced synucleinopathy in heterozygous mice transgenic for human mutant A53T [alpha]-synuclein (line M83). The same was the case when cerebellar extracts from a case of multiple system atrophy with type II [alpha]-synuclein filaments were administered intraperitoneally, intravenously or intramuscularly. We observed abundant immunoreactivity for pS129 [alpha]-synuclein in nerve cells and severe motor impairment, resulting in hindlimb paralysis and shortened lifespan. Filaments immunoreactive for pS129 [alpha]-synuclein were in evidence. A 70% loss of motor neurons was present five months after an intraperitoneal injection of assembled A53T [alpha]-synuclein or cerebellar extract with type II [alpha]-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 [alpha]-synuclein inclusions in nerve cells and neurodegeneration, accompanied by a shift in microglial cell morphology. Propagation of [alpha]-synuclein inclusions depended on the characteristics of both seeds and transgenically expressed protein. Keywords: [alpha]-Synuclein, Multiple system atrophy, Seeded assembly, Neurodegeneration, Microglia