Gut-initiated alpha synuclein fibrils drive parkinsonism phenotypes: temporal mapping of REM sleep behavior disorder-like and other non-motor symptoms.
| Publication Type | Academic Article |
| Authors | Dautan D, Paslawski W, Montejo S, Doyon D, Brioschi V, Marongiu R, Kaplitt M, Chen R, Dawson V, Zhang X, Dawson T, Svenningsson P |
| Journal | Transl Neurodegener |
| Volume | 15 |
| Issue | 1 |
| Date Published | 03/10/2026 |
| ISSN | 2047-9158 |
| Keywords | alpha-Synuclein, REM Sleep Behavior Disorder, Parkinsonian Disorders, Gastrointestinal Tract |
| Abstract | 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. |
| DOI | 10.1186/s40035-026-00536-6 |
| PubMed ID | 41808195 |
| PubMed Central ID | PMC12973632 |