9J4E

Cryo-EM structure of P25alpha full-length fibril

Summary for 9J4E

• Entry DOI: 10.2210/pdb9j4e/pdb
• EMDB information: 61133
• Descriptor: Tubulin polymerization-promoting protein (1 entity in total)
• Functional Keywords: protein fibril, amyloid, cytosolic protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 6
• Total formula weight: 142438.94

Authors

Xia, W.C.,Sun, Y.P.,Huang, C.A.,Liu, C. (deposition date: 2024-08-09, release date: 2025-08-13, Last modification date: 2026-06-03)

Primary citation

Zeng, S.,Zhang, S.,Zhang, S.,Fan, Y.,Xia, W.,Chen, F.,Huang, C.,Lv, S.,Lu, J.,Sun, Y.,Liu, K.,Li, Y.,Zhang, Y.,Wang, J.,Liu, C.,Li, D.
TPPP/p25 amyloid seeding activity as a specific biomarker for multiple system atrophy.
Cell, 2026

PubMed Abstract: Detection of α-synuclein (α-syn) amyloid seeds in human biofluids has attracted great interest for clinical diagnosis of synucleinopathies. However, as a common biomarker, α-syn lacks specificity in reliably differentiating distinct disorders. Here, we report tubulin polymerization promoting protein (TPPP/p25) as a cerebrospinal fluid (CSF) biomarker for the specific diagnosis of multiple system atrophy (MSA). We demonstrate that native TPPP/p25 is self-protected against amyloid aggregation, while disease-related mutation disrupts this protection, triggering TPPP/p25 aggregation. Cryo-electron microscopy (cryo-EM) analysis reveals that the well-folded core domain (CORE) undergoes large conformational changes to mediate amyloid formation. Based on this insight, we developed a seed amplification assay using a minimized CORE (miniCORE) monomer, which detects TPPP/p25 amyloid seeds in CSF and robustly differentiates MSA from Parkinson's disease (PD) and other neurodegenerative diseases. Our findings establish misfolded TPPP/p25 as a promising, specific biomarker in biofluids for MSA diagnosis.

PubMed: 42190663
DOI: 10.1016/j.cell.2026.04.050

Experimental method

ELECTRON MICROSCOPY (3.32 Å)