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

Acta Neuropathologica Communications

Annabelle Grossman¹  Isabelle Lavenir²  Michel Goedert²  Masami Masuda-Suzukake²  Manuel Schweighauser²  Jennifer A. Macdonald²  John L. Chen²  Richard Berks²  Thomas Warner³  Janice L. Holton³  Zane Jaunmuktane³ 

[1] Kymab, Babraham Research Campus, CB22 3AT, Cambridge, UK;MRC Laboratory of Molecular Biology, Francis Crick Avenue, CB2 0QH, Cambridge, UK;Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, 1 Wakefield Street, WC1N 1PJ, London, UK;

关键词: α-Synuclein;    Multiple system atrophy;    Seeded assembly;    Neurodegeneration;    Microglia;   

DOI  :  10.1186/s40478-021-01291-7

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY