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TitleTPPP/p25 amyloid seeding activity as a specific biomarker for multiple system atrophy.
Journal, issue, pagesCell, Year 2026
Publish dateMay 26, 2026
AuthorsShuyi Zeng / Shenqing Zhang / Shengnan Zhang / Yun Fan / Wencheng Xia / Feiyang Chen / Chengan Huang / Shiran Lv / Jinxia Lu / Yunpeng Sun / Kaien Liu / Yunxia Li / Yaoyang Zhang / Jian Wang / Cong Liu / Dan Li /
PubMed AbstractDetection 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 ...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.
External linksCell / PubMed:42190663
MethodsEM (helical sym.)
Resolution2.49 - 3.32 Å
Structure data

61132

9j4d

EMDB-61132, PDB-9j4d:
Cryo-EM structure of P25alpha core fibril
Method: EM (helical sym.) / Resolution: 2.93 Å

61133

9j4e

EMDB-61133, PDB-9j4e:
Cryo-EM structure of P25alpha full-length fibril
Method: EM (helical sym.) / Resolution: 3.32 Å

61134

9j4f

EMDB-61134, PDB-9j4f:
Cryo-EM structure of P25alpha full-length A119V fibril
Method: EM (helical sym.) / Resolution: 2.49 Å

Source
  • homo sapiens (human)
KeywordsCYTOSOLIC PROTEIN / PROTEIN FIBRIL / amyloid

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