Multiple system atrophy-derived α-synuclein fibrils are more potent and display oligodendrocyte cell tropism compared to Parkinson's disease-derived fibrils
Abstract
Multiple System Atrophy (MSA) and Parkinson's Disease (PD) are neurodegenerative diseases characterized by abundant α-synuclein (αSyn) aggregation in the brain. Compared to PD patients, MSA patients have more widespread neurodegeneration and a more aggressive disease course. PD-related αSyn pathology is primarily neuronal, whereas MSA brains characteristically display oligodendroglial inclusions. The strain hypothesis poses that polymorphisms of the αSyn aggregates, so-called strains, may explain disease heterogeneity. The present study investigates the differential properties of αSyn fibrils derived from MSA and PD patients' brains using the protein misfolding cyclic amplification (PMCA) method in cultured neurons and in vivo. MSA- and PD-derived αSyn species were administered to primary murine neuronal cell cultures or injected intrastriatally into wildtype mice, along with de novo generated αSyn fibrils of the ribbon and fibril types. The potency to induce phosphorylated αSyn (pSyn) pathology, microglial reactivity, and the extent of oligodendroglial pSyn pathology were compared among the different seeding materials using immunohistochemical and immunofluorescent approaches. In summary, the various seeding materials induced pSyn pathology of distinguishable potency and morphology. PMCA-derived material from MSA brains and the fibril polymorph induced more pSyn pathology in both neuronal cultures and in mice compared to PMCA-derived material from PD brains and the ribbon polymorph. Interestingly, amplified material from MSA brains induced significantly more oligodendroglial pSyn aggregates than amplified material from PD brains. Additionally, mice injected with the fibril polymorph, showed mild changes in microglial reactivity. Our findings suggest specific properties of the MSA- and PD-derived fibrils, and overall support the strain hypothesis.
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BibTeX
@article{laursen2026multiple,
title = {{Multiple system atrophy-derived α-synuclein fibrils are more potent and display oligodendrocyte cell tropism compared to Parkinson's disease-derived fibrils}},
author = {Anne-Line Strange Laursen and Katarina Willén and Alexis Fenyi and Christiane Volbracht and Louise Torp Dalgaard and Susana Aznar and Ronald Melki and Karina Fog and Florence Sotty},
journal = {Neurobiology of Disease},
year = {2026},
month = aug,
doi = {10.1016/j.nbd.2026.107575},
url = {https://cnrs.hal.science/hal-05758476v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Multiple system atrophy-derived α-synuclein fibrils are more potent and display oligodendrocyte cell tropism compared to Parkinson's disease-derived fibrils
AU - Anne-Line Strange Laursen
AU - Katarina Willén
AU - Alexis Fenyi
AU - Christiane Volbracht
AU - Louise Torp Dalgaard
AU - Susana Aznar
AU - Ronald Melki
AU - Karina Fog
AU - Florence Sotty
PY - 2026
DA - 2026/08/14
JO - Neurobiology of Disease
DO - 10.1016/j.nbd.2026.107575
UR - https://cnrs.hal.science/hal-05758476v1
AB - Multiple System Atrophy (MSA) and Parkinson's Disease (PD) are neurodegenerative diseases characterized by abundant α-synuclein (αSyn) aggregation in the brain. Compared to PD patients, MSA patients have more widespread neurodegeneration and a more aggressive disease course. PD-related αSyn pathology is primarily neuronal, whereas MSA brains characteristically display oligodendroglial inclusions. The strain hypothesis poses that polymorphisms of the αSyn aggregates, so-called strains, may explain disease heterogeneity. The present study investigates the differential properties of αSyn fibrils derived from MSA and PD patients' brains using the protein misfolding cyclic amplification (PMCA) method in cultured neurons and in vivo. MSA- and PD-derived αSyn species were administered to primary murine neuronal cell cultures or injected intrastriatally into wildtype mice, along with de novo generated αSyn fibrils of the ribbon and fibril types. The potency to induce phosphorylated αSyn (pSyn) pathology, microglial reactivity, and the extent of oligodendroglial pSyn pathology were compared among the different seeding materials using immunohistochemical and immunofluorescent approaches. In summary, the various seeding materials induced pSyn pathology of distinguishable potency and morphology. PMCA-derived material from MSA brains and the fibril polymorph induced more pSyn pathology in both neuronal cultures and in mice compared to PMCA-derived material from PD brains and the ribbon polymorph. Interestingly, amplified material from MSA brains induced significantly more oligodendroglial pSyn aggregates than amplified material from PD brains. Additionally, mice injected with the fibril polymorph, showed mild changes in microglial reactivity. Our findings suggest specific properties of the MSA- and PD-derived fibrils, and overall support the strain hypothesis.
SN - 0969-9961
SN - 1095-953X
ER -