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Probe-dependent Proximity Profiling (ProPPr) Uncovers Similarities and Differences in Phospho-Tau-Associated
Dmytro Morderer1, Melissa C Wren1, Feilin Liu1
1Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Molecular Neurodegeneration
|March 14, 2025
Summary
This study reveals the diverse protein compositions of tau aggregates in neurodegenerative diseases like Alzheimer's. The new ProPPr method identifies disease-specific proteins, aiding biomarker and therapy development for tauopathies.
Area of Science:
- Neuroscience
- Proteomics
- Biochemistry
Background:
- Tauopathies are neurodegenerative diseases defined by abnormal tau protein aggregation.
- Mechanisms driving diverse tau pathology in neurons and glia remain unclear.
- Specific protein composition of tau lesions across different tauopathies is largely unknown.
Purpose of the Study:
- To investigate the protein composition of tau aggregates in four major tauopathies: Alzheimer's disease (AD), corticobasal degeneration (CBD), Pick's disease (PiD), and progressive supranuclear palsy (PSP).
- To characterize the proteomic landscape associated with distinct tau lesions.
- To identify disease-specific proteins involved in tau pathogenesis.
Main Methods:
- Developed Probe-dependent Proximity Profiling (ProPPr) for in situ proximity labeling and isolation of aggregate-associated proteins from FFPE human brain tissue.
- Analyzed proteomes of AT8-positive lesions using data-independent acquisition mass spectrometry.
- Validated protein associations through co-immunofluorescence staining and quantitative imaging.
Main Results:
- Identified common and tauopathy-specific proteins associated with phospho-tau aggregates.
- Revealed associations of VPS35 and LAMP2 with specific phospho-tau lesions.
- Discovered disease-specific proteins including GSK3α, FTL, and VGF, with FTL-positive microglia noted in CBD lesions.
Conclusions:
- ProPPr is effective for unbiased discovery of local proteomes in FFPE tissue, offering insights into tauopathy mechanisms.
- Comprehensive characterization of tau-associated proteomes enhances understanding of disease heterogeneity.
- Findings inform strategies for developing diagnostic biomarkers and targeted therapies for tauopathies.
