TPPP/p25 amyloid seeding activity as a specific biomarker for multiple system atrophy
Summary
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 aggregatio
Content
# TPPP/p25 amyloid seeding activity as a specific biomarker for multiple system atrophy
*Published: 2026 May 26*
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.
DOI: 10.1016/j.cell.2026.04.050