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TPPP/p25 amyloid seeding activity as a specific biomarker for multiple system atrophy
Shuyi Zeng1, Shenqing Zhang1, Shengnan Zhang2
1Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China; Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai 200240, China.
Tubulin polymerization promoting protein (TPPP/p25) in cerebrospinal fluid shows promise as a specific biomarker for multiple system atrophy (MSA). This new diagnostic tool differentiates MSA from Parkinson
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Alpha-synuclein (α-syn) seeds in biofluids are key for diagnosing synucleinopathies but lack specificity.
- Distinguishing between different neurodegenerative disorders like multiple system atrophy (MSA) and Parkinson's disease (PD) remains a clinical challenge.
Purpose of the Study:
- To identify a specific cerebrospinal fluid (CSF) biomarker for the accurate diagnosis of MSA.
- To investigate the aggregation mechanism of tubulin polymerization promoting protein (TPPP/p25) and develop a diagnostic assay.
Main Methods:
- Utilized cryo-electron microscopy (cryo-EM) to analyze TPPP/p25 structure and aggregation.
- Developed a seed amplification assay using a minimized CORE (miniCORE) monomer of TPPP/p25.
- Tested the assay's efficacy in detecting TPPP/p25 amyloid seeds in human CSF samples.
Main Results:
- Identified TPPP/p25 as a specific biomarker for MSA in CSF.
- Demonstrated that native TPPP/p25 is protected from aggregation, while mutations trigger it.
- The miniCORE-based assay successfully differentiated MSA from PD and other neurodegenerative diseases using CSF.
Conclusions:
- Misfolded TPPP/p25 serves as a specific and promising biomarker for MSA diagnosis in biofluids.
- The developed seed amplification assay offers a robust method for differentiating MSA.
- Understanding TPPP/p25 aggregation provides insights into disease mechanisms and diagnostic strategies.
