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Seeing Invisible Oligomers: Rethinking α-Synuclein Pathology Through Proximity Ligation Assay.

Hiroaki Sekiya¹, Nanna Møller Jensen^2,3,4, Dennis W Dickson¹

¹Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.

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Summary

Parkinson's disease pathology involves more than just visible inclusions. The α-synuclein proximity ligation assay (αSYN-PLA) detects soluble oligomers, revealing widespread neurotoxic species previously missed in synucleinopathies.

Keywords:

Multiple System Atrophy Parkinson's disease non‐inclusion pathology oligomers proximity ligation assay α‐synuclein

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Published on: June 23, 2022

Area of Science:

Neuroscience
Pathology
Biochemistry

Background:

Parkinson's disease (PD) and multiple system atrophy are characterized by α-synuclein (αSYN)-positive inclusions.
However, these inclusions constitute only a portion of the disease-relevant pathology.
Soluble oligomeric αSYN assemblies are increasingly recognized as key neurotoxic species, often undetectable by standard methods.

Purpose of the Study:

To introduce and discuss the αSYN proximity ligation assay (αSYN-PLA) for detecting non-inclusion αSYN pathology.
To review the principles, antibody strategies, and structural implications of αSYN-PLA.
To explore the clinical applications of PLA-detected αSYN aggregates as biomarkers and therapeutic targets.

Main Methods:

Utilizing the αSYN proximity ligation assay (αSYN-PLA) for in situ detection of αSYN oligomers.
Applying αSYN-PLA to study synucleinopathies, including LRRK2-associated PD.
Analyzing antibody strategies and structural characteristics of detected αSYN species.

Main Results:

αSYN-PLA enables the detection of widespread non-inclusion oligomeric αSYN pathology in synucleinopathies.
Studies in LRRK2-associated PD reveal abundant oligomeric αSYN even in cases lacking Lewy bodies (LBs).
This challenges the traditional focus on inclusions as the sole indicator of disease.

Conclusions:

Soluble oligomeric αSYN species, detectable by αSYN-PLA, represent a significant component of neurotoxic pathology.
αSYN-PLA offers a novel approach to understanding synucleinopathies beyond conventional inclusion detection.
PLA-positive aggregates hold potential as future biomarkers and therapeutic targets for PD and related disorders.