Gut-initiated alpha synuclein fibrils drive parkinsonism phenotypes: temporal mapping of REM sleep behavior disorder-like and other non-motor symptoms.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by both motor and non-motor symptoms. Although non-motor features such as gastrointestinal and sleep disturbances often precede motor impairments and are critical to PD pathogenesis, the mechanisms underlying their onset and progression remain insufficiently characterized. METHODS: To investigate the sequential development of motor and non-motor symptoms in a model of experimental parkinsonism, we injected alpha-synuclein (αSyn) preformed fibrils (PFFs) into the duodenum and antrum of wild-type mice, establishing a gut-brain axis model of PD. We performed whole-brain anatomical mapping of αSyn-PFF propagation and assessed behavioral alterations at multiple time points post-injection. Correlations between anatomical spread and behavioral changes, particularly sleep, were further validated through SNCA overexpression or local αSyn-PFF injections in the substantia nigra, combined with dual-wavelength fiber photometry, behavioral assays, and histological analyses. RESULTS: Injection of αSyn-PFFs into the gastrointestinal tract of wild-type mice led to a progressive spread of pathological αSyn throughout the central nervous system, in temporal association with distinct motor and non-motor phenotypes. These findings provide translational validity of the gut-brain model, mirroring the clinical progression seen in many PD patients. In two established αSyn-based PD models, dual-wavelength fiber photometry that monitors dopamine and acetylcholine release in the striatum, demonstrated a central role for dopamine dysfunction in modulating sleep architecture, particularly in relation to REM sleep without atonia, consistent with REM sleep behavior disorder (RBD)-like manifestations in PD. CONCLUSION: This work provides a detailed characterization of the progressive and multisystem nature of experimental parkinsonism, highlighting the interplay between αSyn pathology, gut-brain signaling, and the onset of non-motor disturbances, with a particular focus on RBD-like alterations in sleep.