The Parkinson's disease-associated A53E mutation decreases alpha-synuclein aggregation and phosphorylation in vivo
- 1Lewis & Clark College
Abstract
Abnormal -synuclein aggregation is the defining feature of Parkinson's disease (PD) and related synucleinopathies. Rare disease-causing alpha-synuclein mutations either accelerate or slow fibrillization in vitro, however their effects in vivo are less well understood. Interestingly, the A53E mutation slows fibrillization in vitro but causes a more virulent form of PD. We use an in vivo model to examine the aggregation dynamics of disease-causing A53E and E46K alpha-synuclein mutations. Fluorescence recovery after photobleaching within presynaptic terminals shows that A53E-alpha-synuclein is significantly more mobile than E46K- or wild-type (WT)-alpha-synuclein. Longitudinal analysis in vivo reveals that E46K- and WT-alpha-synuclein become progressively less mobile over days, while A53E maintains high mobility, suggesting delayed progression toward aggregated states. We also find that A53E-alpha-synuclein lacks detectable disease-relevant phosphorylation at serine-129, unlike E46K-and WT-alpha-synuclein. To mechanistically test whether this unique lack of phosphorylation drives its high mobility, we genetically modified A53E-alpha-synuclein to mimic S129 phosphorylation, and show that this manipulation indeed decreases its mobility, directly implicating the phosphorylation status of this residue in mobility.
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BibTeX
@misc{irving2026parkinsons,
title = {{The Parkinson's disease-associated A53E mutation decreases alpha-synuclein aggregation and phosphorylation in vivo}},
author = {W. L. Irving and S. Meredith-Andrews and K. T. Nguyen and K. L. Schainker and N. L. Brockway and V. K. Unni and T. A. Weissman},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.29.762882},
url = {https://www.biorxiv.org/content/10.64898/2026.10.29.762882v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - The Parkinson's disease-associated A53E mutation decreases alpha-synuclein aggregation and phosphorylation in vivo
AU - W. L. Irving
AU - S. Meredith-Andrews
AU - K. T. Nguyen
AU - K. L. Schainker
AU - N. L. Brockway
AU - V. K. Unni
AU - T. A. Weissman
PY - 2026
DA - 2026/10/29
PB - bioRxiv
DO - 10.64898/2026.10.29.762882
UR - https://www.biorxiv.org/content/10.64898/2026.10.29.762882v1
AB - Abnormal -synuclein aggregation is the defining feature of Parkinson's disease (PD) and related synucleinopathies. Rare disease-causing alpha-synuclein mutations either accelerate or slow fibrillization in vitro, however their effects in vivo are less well understood. Interestingly, the A53E mutation slows fibrillization in vitro but causes a more virulent form of PD. We use an in vivo model to examine the aggregation dynamics of disease-causing A53E and E46K alpha-synuclein mutations. Fluorescence recovery after photobleaching within presynaptic terminals shows that A53E-alpha-synuclein is significantly more mobile than E46K- or wild-type (WT)-alpha-synuclein. Longitudinal analysis in vivo reveals that E46K- and WT-alpha-synuclein become progressively less mobile over days, while A53E maintains high mobility, suggesting delayed progression toward aggregated states. We also find that A53E-alpha-synuclein lacks detectable disease-relevant phosphorylation at serine-129, unlike E46K-and WT-alpha-synuclein. To mechanistically test whether this unique lack of phosphorylation drives its high mobility, we genetically modified A53E-alpha-synuclein to mimic S129 phosphorylation, and show that this manipulation indeed decreases its mobility, directly implicating the phosphorylation status of this residue in mobility.
SN - 2692-8205
ER -