Phosphorylated -Synuclein shapes changes in brain structure, task-related activity and functional connectivity in M83 mice
- 1Western University
Abstract
Phosphorylated -synuclein at S129 (pS129) is the predominant form of -synuclein in the aggregates known as Lewy bodies (LB) and Lewy neurites (LN), the pathological hallmarks of Parkinson's disease (PD) and dementia with Lewy bodies (DLB), collectively known as synucleinopathies. The toxic nature of these inclusions remains contentious. To improve our understanding of these aggregates and their role in the structural and functional changes observed in synucleinopathies, we combined non-invasive structural and functional MRI in awake head-fixed M83 mice with whole-brain light-sheet fluorescence microscopy (LSFM) in the same animals following a unilateral injection of either human preformed fibrils of -synuclein (PFF) or PBS into the dorsal striatum. We developed a multimodal framework integrating the non-invasive, mesoscopic nature of MRI with the cellular-level details of LSFM to further our understanding of the underlying pathology of synucleinopathies. Using this framework, we show that four months after injection, animals injected with PFFs showed ubiquitous spread of pS129 pathology throughout the whole brain and spinal cord consistent with anatomical connectivity from the seeding region, with some structures such as the midbrain more susceptible to pS129 accumulation. Compared to controls, PFF-injected animals showed widespread atrophy as well as a decrease in functional connectivity, while evoked activity in the somatosensory/somatomotor areas in response to spontaneous paw movements showed significant hypoactivation. These cellular, structural and functional changes were significantly associated with the proportion of pS129 accumulation determined in the same animals. Our results demonstrate the deleterious effects of pS129 accumulation and argue in favor of a toxic role played by these aggregates.
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BibTeX
@misc{eed2026phosphorylated,
title = {{Phosphorylated -Synuclein shapes changes in brain structure, task-related activity and functional connectivity in M83 mice}},
author = {A. Eed and V. Novikov and S. Bahrampour and K. Summers and S. Tullo and M. Chakravarty and W. Luo and I. Shlaifer and T. M. Durcan and V. F. Prado and A. R. Khan and M. A. M. Prado and R. S. Menon},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.16.752140},
url = {https://www.biorxiv.org/content/10.64898/2026.09.16.752140v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Phosphorylated -Synuclein shapes changes in brain structure, task-related activity and functional connectivity in M83 mice
AU - A. Eed
AU - V. Novikov
AU - S. Bahrampour
AU - K. Summers
AU - S. Tullo
AU - M. Chakravarty
AU - W. Luo
AU - I. Shlaifer
AU - T. M. Durcan
AU - V. F. Prado
AU - A. R. Khan
AU - M. A. M. Prado
AU - R. S. Menon
PY - 2026
DA - 2026/09/16
PB - bioRxiv
DO - 10.64898/2026.09.16.752140
UR - https://www.biorxiv.org/content/10.64898/2026.09.16.752140v1
AB - Phosphorylated -synuclein at S129 (pS129) is the predominant form of -synuclein in the aggregates known as Lewy bodies (LB) and Lewy neurites (LN), the pathological hallmarks of Parkinson's disease (PD) and dementia with Lewy bodies (DLB), collectively known as synucleinopathies. The toxic nature of these inclusions remains contentious. To improve our understanding of these aggregates and their role in the structural and functional changes observed in synucleinopathies, we combined non-invasive structural and functional MRI in awake head-fixed M83 mice with whole-brain light-sheet fluorescence microscopy (LSFM) in the same animals following a unilateral injection of either human preformed fibrils of -synuclein (PFF) or PBS into the dorsal striatum. We developed a multimodal framework integrating the non-invasive, mesoscopic nature of MRI with the cellular-level details of LSFM to further our understanding of the underlying pathology of synucleinopathies. Using this framework, we show that four months after injection, animals injected with PFFs showed ubiquitous spread of pS129 pathology throughout the whole brain and spinal cord consistent with anatomical connectivity from the seeding region, with some structures such as the midbrain more susceptible to pS129 accumulation. Compared to controls, PFF-injected animals showed widespread atrophy as well as a decrease in functional connectivity, while evoked activity in the somatosensory/somatomotor areas in response to spontaneous paw movements showed significant hypoactivation. These cellular, structural and functional changes were significantly associated with the proportion of pS129 accumulation determined in the same animals. Our results demonstrate the deleterious effects of pS129 accumulation and argue in favor of a toxic role played by these aggregates.
ER -