TAF15 RNA-binding protein forms prion-like amyloid fibrils via specific low-complexity domain motifs in FTLD.
Background
The accumulation of misfolded proteins is a hallmark of many neurodegenerative diseases, including Frontotemporal Lobar Degeneration (FTLD). A subset of FTLD cases is characterized by aggregates of TATA-box binding protein-associated factor 15 (TAF15), an RNA-binding protein. However, the precise molecular mechanisms driving TAF15 aggregation and its role in disease progression remain poorly understood. Understanding these determinants is crucial for developing targeted therapies for FTLD-TAF15, as current treatments primarily offer symptomatic relief.
Study Design
Researchers investigated TAF15 aggregation by first demonstrating its ability to form amyloid fibrils under physiological conditions. They then developed a novel cellular biosensor system to monitor TAF15 propagation. This system was challenged with both recombinant TAF15 fibrils and pathological TAF15 aggregates extracted from post-mortem FTLD patient brains. To assess specificity, the closely related protein FUS was also tested for its ability to cross-seed TAF15 aggregation. Computational analysis and peptide-based mapping were employed to identify specific aggregation-prone motifs within the low-complexity domain of TAF15.
Results
TAF15 was confirmed to form amyloid fibrils under physiological conditions, a critical step in its pathological role. Using a novel cellular biosensor, the study demonstrated that both recombinant TAF15 fibrils and pathological aggregates from FTLD patient brains selectively seeded TAF15 aggregation, exhibiting clear prion-like properties. This seeding was specific, as the closely related protein FUS did not induce TAF15 aggregation, indicating a cross-seeding barrier. However, FUS was observed to partially incorporate into inclusions during TAF15-induced seeding, potentially explaining their pathological overlap in FTLD. Computational and peptide-based mapping precisely identified specific aggregation-prone motifs within the low-complexity domain of TAF15. These motifs were found to be crucial for stabilizing ex vivo fibril cores and directly driving TAF15 propagation. The findings establish TAF15 as an amyloid-forming, prion-like protein.
These aggregation-prone motifs within the
low-complexity domainare critical for stabilizing TAF15 fibril cores and driving its self-assembly and propagation.
Key Findings
- TAF15 forms amyloid fibrils under physiological conditions.
- Both recombinant TAF15 fibrils and FTLD patient aggregates exhibit prion-like seeding of TAF15 in biosensor cells.
- FUS does not cross-seed TAF15 aggregation but can incorporate into TAF15 inclusions.
- Computational and peptide mapping identified specific aggregation-prone motifs in TAF15's low-complexity domain.
- These motifs stabilize fibril cores and drive TAF15 propagation.
Why It Matters
This research fundamentally changes our understanding of TAF15's role in FTLD, establishing it as a prion-like protein. For researchers and drug developers, identifying the specific aggregation-prone motifs within TAF15's low-complexity domain provides concrete targets for therapeutic intervention. This mechanistic framework could lead to the development of novel small molecules or biologics designed to inhibit TAF15 aggregation or propagation, potentially slowing or halting disease progression in FTLD-TAF15. While still preclinical, this work lays the groundwork for future drug discovery efforts, moving us closer to a usable protocol for preventing or treating this devastating neurodegenerative condition.
taf15
ftld
frontotemporal-lobar-degeneration
amyloid
prion-like
protein-aggregation