Bilateral intranigral α-synuclein seeding in A53T transgenic mice drives early Parkinsonism and concurrent gut dysbiosis.

Heterozygous A53T α-synuclein transgenic mice (M83 line) typically exhibit late-onset Parkinson's disease (PD) symptoms. This study established an accelerated PD model via bilateral intranigral injection of α-synuclein preformed fibrils (PFF) to characterize central and peripheral pathologies. Three-month-old heterozygous A53T mice received bilateral substantia nigra injections of α-synuclein PFF or PBS. Motor function was assessed monthly. Following the onset of motor deficits, the substantia nigra was harvested for immunohistochemistry and colons were harvested for H&E, transcriptomic analysis and western blotting, while gut microbiota composition was assessed using metagenomic sequencing. Three months post-injection, PFF-treated mice exhibited significant motor deficits, dopaminergic neuron loss, and nigral α-synuclein aggregation, with no sex differences. Peripherally, mice displayed increased α-synuclein in colon, impaired gut motility, reduced Occludin expression indicating barrier damage, and colonic inflammation. Metagenomics identified gut dysbiosis characterized by a skewed Bacillota/Bacteroidota ratio, Lactobacillus depletion, and enrichment of inflammation-associated taxa. Bilateral intranigral α-synuclein PFF injection in A53T mice successfully induces an early-onset, progressive PD phenotype encompassing motor impairments, nigrostriatal neurodegeneration. Crucially, the model recapitulates key peripheral manifestations, including gastrointestinal dysfunction and microbial dysbiosis. These findings provide compelling evidence for a descending brain-to-gut pathological axis where central α-synuclein pathology drives distal gut alterations. This optimized model offers a valuable platform for investigating multi-system PD progression and bidirectional brain-gut communication mechanisms.