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Published on: December 8, 2015
Aggregation and propagation of TAF15 trigger neurodegeneration
Lanxia Meng1, Congcong Liu1, Huangchuan Gong1
1Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
Abstract:
Protein misfolding and propagation contribute to neurodegenerative diseases. Recently, cryogenic electron microscopy of insoluble amyloid fibrils derived from individuals with frontotemporal lobar degeneration (FTLD) revealed new species of amyloid fibrils, which are composed of aggregated TATA-binding protein-associated factor 15 (TAF15). However, it remains unknown whether TAF15 fibrils propagate in a prion-like manner and drive neurodegeneration. Here, we show that TAF15 forms amyloid fibrils that can self-propagate. Strikingly, a single injection of synthetic TAF15 pre-formed fibrils into the prefrontal cortex of wild-type mice led to the aggregation of endogenous TAF15 and cell-to-cell transmission of pathologic TAF15. TAF15 pathology was accompanied by progressive degeneration of cortical neurons, cognitive impairments, and anxiety- and depression-like behaviors. The detrimental effects of TAF15 fibrils were abolished by genetic deletion of endogenous TAF15. Together, these observations indicate that TAF15 aggregation drives neurodegeneration.
Insights
TATA-binding protein-associated factor 15 (TAF15) forms self-propagating amyloid fibrils. These fibrils cause neurodegeneration and cognitive deficits in mice, indicating TAF15 aggregation drives disease.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Protein misfolding and aggregation are implicated in neurodegenerative diseases.
- Frontotemporal lobar degeneration (FTLD) involves amyloid fibril formation.
- The role of TATA-binding protein-associated factor 15 (TAF15) in neurodegeneration is unclear.
Purpose of the Study:
- To investigate if TAF15 amyloid fibrils propagate in a prion-like manner.
- To determine if TAF15 aggregation drives neurodegeneration.
Main Methods:
- Induction of TAF15 amyloid fibril formation in vitro.
- Stereotactic injection of synthetic TAF15 fibrils into wild-type mouse brains.
- Assessment of endogenous TAF15 aggregation and pathology.
- Behavioral testing (cognitive, anxiety, depression) in mice.
- Genetic deletion of endogenous TAF15 to assess protective effects.
Main Results:
- Synthetic TAF15 fibrils were shown to self-propagate.
- Injection of TAF15 fibrils induced aggregation of endogenous TAF15 and cell-to-cell transmission.
- TAF15 pathology led to cortical neuron degeneration, cognitive impairment, and behavioral deficits.
- Genetic deletion of TAF15 abolished the detrimental effects of TAF15 fibrils.
Conclusions:
- TAF15 amyloid fibrils can self-propagate and induce neurodegeneration.
- TAF15 aggregation is a causative factor in neurodegenerative processes.
- TAF15 represents a potential therapeutic target for related neurodegenerative diseases.
