Multiple system atrophy brain regional specific alpha-synuclein pathologies impact seeding potency and propagation

Multiple system atrophy (MSA) is a synucleinopathy characterized by regionally and cellularly heterogeneous α-synuclein (αsyn) pathology. Although MSA-derived brain lysates can robustly seed αsyn pathology in experimental models, the extent to which the anatomical origin of pathogenic seeds influences pathological induction and propagation remains unclear. Previous studies suggest that the cellular environment in which αsyn aggregates form may influence their seeding properties. Here, Triton X-100-insoluble brain lysates derived from the cerebellum and pons of two neuropathologically confirmed MSA donors were stereotaxically inoculated into the hippocampus of TgM20 mice expressing human wild-type αsyn to compare their seeding properties in vivo . Cerebellar white matter lysates, which are predominantly enriched in αsyn oligodendroglial glial cytoplasmic inclusion (GCI) pathology, induced broader and more robust early αsyn pathology than pontine lysates, which contained both αsyn neuronal and oligodendroglial inclusion pathology. These differences were most apparent at 4 months post-inoculation and were particularly evident with antibodies recognizing C-terminally truncated αsyn species. By 8 months post-inoculation, the overall anatomical distributions of induced αsyn pathology were more comparable between lysate groups; however, cerebellar lysates continued to produce greater spinal cord pathology, and temporal analyses identified lysate-dependent differences in progression in selected antibody and regional readouts. Oligodendroglial αsyn inclusions were also observed within Olig2-positive cells in the corpus callosum following inoculation with both lysate types. Collectively, these findings demonstrate that the anatomical origin of MSA-derived brain lysates influences the induction and propagation of αsyn pathology in vivo . Although the regional differences are consistent with a potential contribution of the cellular composition of the donor pathology, the present experiments do not directly isolate GCI- from αsyn neuronal cytoplasmic inclusion-derived seeds, thus the involvement of other molecular factors cannot be excluded.