A novel brainstem-targeted G51D α-synuclein fibril-injected mouse model exhibits sequential emergence of sleep and motor dysfunction.

Abnormal accumulation of alpha-synuclein (α-syn) is a central pathologic hallmark of synucleinopathies such as Parkinson's disease (PD), with rapid eye movement sleep behavior disorder (RBD) widely recognized as a prodromal manifestation of these disorders. Although several mouse models recapitulate the α-syn pathology, most fail to reproduce the brainstem-originating pathology propagation proposed by Braak and do not exhibit the RBD-like phenotypes expected in the prodromal phase. Here, we focused on the G51D mutation of α-syn, a familial PD-associated variant that leads to early disease onset and severe clinical symptoms. We microinjected G51D mutant α-syn fibrils into the pontine tegmental area of the brainstem in mice, a region critically involved in REM sleep regulation, and evaluated the effects on sleep architecture, pathologic progression, and motor function. Our results revealed that microinjection of G51D fibrils into the brainstem induces more extensive pathologic changes compared with wild-type fibrils and leads to the sequential emergence of RBD-like behaviors, motor deficits, and dopaminergic neuronal loss. These findings support the hypothesis that the G51D mutation worsens disease severity and establish this model as a valuable tool for investigating the mechanisms underlying synucleinopathies and their prodromal symptoms.