Gut-initiated alpha synuclein fibrils drive parkinsonism phenotypes: temporal mapping of REM sleep behavior disorder-like and other non-motor symptoms.
Overview
- Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden
- Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815 USA
- Department of Neurological Surgery, Weill Cornell Medicine, New York, NY USA
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD USA
- Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD USA
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA
- Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD USA
- Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD USA
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.
Supplementary Information: The online version contains supplementary material available at 10.1186/
Reproduced under the paper's license (CC BY), from the paper cited above.
Code
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Data
Datasets cited
- figshare:31641546, at figshare; found in DataCite
- figshare:31641549, at figshare; found in DataCite
- zenodo:10822457, at Zenodo; found in “Data sharing”
Data sharing
Detailed protocols are available on the https://
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.
Version 1, 30 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 12 authors, 5 keywords, 10 MeSH terms, 3 funders, 83 references, 4 RRIDs.
Cite
This paper
Dautan, D., Paslawski, W., Montejo, S. G., Doyon, D. C., Brioschi, V. I., Marongiu, R., Kaplitt, M. G., Chen, R., Dawson, V. L., Zhang, X., Dawson, T. M., & Svenningsson, P. (2026). Gut-initiated alpha synuclein fibrils drive parkinsonism phenotypes: temporal mapping of REM sleep behavior disorder-like and other non-motor symptoms. Translational neurodegeneration, 15(1), 10. https://
BibTeX
@article{dautan2026gut,
author = {Dautan, Daniel and Paslawski, Wojciech and Montejo, Sergio G and Doyon, Daniel C and Brioschi, Valentina I and Marongiu, Roberta and Kaplitt, Michael G and Chen, Rong and Dawson, Valina L and Zhang, Xiaoqun and Dawson, Ted M and Svenningsson, Per},
title = {{Gut-initiated alpha synuclein fibrils drive parkinsonism phenotypes: temporal mapping of REM sleep behavior disorder-like and other non-motor symptoms}},
journal = {Translational neurodegeneration},
year = {2026},
month = mar,
volume = {15},
number = {1},
pages = {10},
publisher = {BMC},
issn = {2047-9158},
doi = {10.1186/
url = {https://
pmid = {41808195},
pmcid = {PMC12973632}
}
RIS
TY - JOUR
AU - Dautan, Daniel
AU - Paslawski, Wojciech
AU - Montejo, Sergio G
AU - Doyon, Daniel C
AU - Brioschi, Valentina I
AU - Marongiu, Roberta
AU - Kaplitt, Michael G
AU - Chen, Rong
AU - Dawson, Valina L
AU - Zhang, Xiaoqun
AU - Dawson, Ted M
AU - Svenningsson, Per
TI - Gut-initiated alpha synuclein fibrils drive parkinsonism phenotypes: temporal mapping of REM sleep behavior disorder-like and other non-motor symptoms
T2 - Translational neurodegeneration
J2 - Transl Neurodegener
PY - 2026
DA - 2026/
VL - 15
IS - 1
SP - 10
SN - 2047-9158
PB - BMC
DO - 10.1186/
UR - https://
LA - en
ER -
CSL-JSON
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