Abstract / Summary
Abstract Rapid eye movement sleep behavior disorder is a strong prodromal predictor of α-synucleinopathies, including Parkinson’s disease, and has been associated with a body-first subtype thought to originate in brainstem and autonomic networks. Here, we investigated whether bilateral α-Synuclein preformed fibril seeding in the sublaterodorsal tegmental nucleus, a brainstem region involved in REM sleep muscle atonia, induces REM sleep behavior disorder-like features and progressive Parkinson’s disease-relevant dysfunction in male wild-type C57BL/6J mice. Mice injected with phosphate-buffered saline or α-Synuclein preformed fibrils ( n = 17) underwent longitudinal EEG/EMG recordings, behavioral testing and post-mortem molecular analyses for up to 15 months post-injection. Seeding induced robust and persistent pS129-α-Synuclein aggregation that propagated across multiple brain regions, including the amygdala and substantia nigra. However, pathology was not accompanied by altered sleep-wake architecture, REM-associated muscle activity, anxiety-like behavior, gastrointestinal dysfunction or motor impairment. No retrograde pS129-α-Synuclein pathology was detected in the enteric nervous system, and nigrostriatal TH immunoreactivity remained preserved. Persistent pathology was also not associated with chronic microglial activation or MHC-II upregulation. Together, these results reveal a striking dissociation between pS129-α-Synuclein aggregation and phenotypic outcome, suggesting that additional susceptibility factors are required for α-Synuclein pathology to progress toward clinically relevant dysfunction in wild-type mice.