<title>Abstract</title>
BackgroundParkinson’s disease (PD) is the most common neurodegenerative movement disorder. Pathological features of PD include dopaminergic neuron loss in the substantia nigra pars compacta (SNpc) and intraneuronal α-Synuclein (α-Syn) inclusions called Lewy bodies (LBs). Since there is no treatment to either halt or slow the progression of PD, it is highly demanded to establish a rodent model that recapitulates the clinicopathological features of PD within a short period to efficiently investigate the pathological mechanisms and test disease-modifying therapies (DMTs).MethodsWe injected human and mouse α-Syn-preformed fibrils (hPFFs and mPFFs, respectively) into the hemilateral dorsal striatum of wild-type mice, wild-type human α-Syn bacterial artificial chromosome (BAC) transgenic (WT BAC-<italic>SNCA</italic> Tg) mice, and A53T human α-Syn BAC transgenic (A53T BAC-<italic>SNCA</italic> Tg) mice, and conducted pathological and behavioral analyses.ResultsWT BAC-<italic>SNCA</italic> Tg and A53T BAC-<italic>SNCA</italic> Tg mice expressed a comparable amount of α-Syn (2.9 and 2.7-fold more α-Syn, respectively, than wild-type mice) in the brains. mPFF injections induced more severe α-Syn pathology in most brain regions, including the ipsilateral SNpc, than hPFF injections in all genotypes at 1 month post-injection. Among the mPFF-injected mice, the A53T BAC-<italic>SNCA</italic> Tg mice exhibited the most severe α-Syn pathology as early as 0.5 month (2 weeks) post-injection. Consistent with these observations, <italic>in vitro</italic> fibrillization assay revealed that a mixture of A53T human α-Syn and mouse α-Syn seeded with mPFFs aggregated most rapidly among the conditions tested. The mPFF-injected A53T BAC-<italic>SNCA</italic> Tg mice showed a 38% reduction in tyrosine hydroxylase (TH)-positive neurons in the ipsilateral SNpc, apomorphine-induced rotational behavior, and motor dysfunction at 2 months post-injection. Notably, the reduction in TH-positive density in the striatum and microglial activation preceded the obvious TH-positive neuron loss in the SNpc.ConclusionsOur data indicate that the extent of α-Syn pathology induced by α-Syn PFF injection depends on the types of α-Syn PFFs and exogenously expressed α-Syn in Tg mice. The mPFF-injected A53T BAC-<italic>SNCA</italic> Tg mice recapitulate the pathological processes of PD more rapidly than previously reported mouse models, suggesting their usefulness for testing DMTs as well as analyzing the pathological mechanisms.