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

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BackgroundParkinson'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.MethodsTo 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.ResultsInjection 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.ConclusionThis 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.

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