Deubiquitinating Enzymes Ubiquitin-Specific Proteases 7 and 10 Regulate TAU Aggregation

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Microtubule-associated protein TAU aggregation is a hallmark of tauopathies, including Alzheimer's disease (AD).
• Impaired protein degradation and altered ubiquitination are implicated in pathological TAU accumulation.
• Deubiquitinating enzymes (DUBs) play a critical role in regulating protein stability and degradation pathways.

Purpose of the Study:

• To investigate the role of DUBs in pathological TAU aggregation.
• To identify specific DUBs that modulate TAU accumulation in tauopathies.
• To explore potential therapeutic targets for reducing pathological TAU.

Main Methods:

• Conducted siRNA knockdown screens of 93 murine DUBs in rTg4510 cortical cultures.
• Utilized pharmacological inhibition of identified DUBs (Usp7 and Usp10).
• Assessed TAU aggregation and ubiquitination levels in various neuronal models, including cortical cultures, hippocampal slice cultures, and wildtype neurons seeded with AD-derived TAU.

Main Results:

• Knockdown and inhibition of ubiquitin-specific proteases 7 (Usp7) and 10 (Usp10) significantly reduced seeded TAU aggregation.
• Soluble TAU levels remained unaffected by Usp7 and Usp10 inhibition.
• Inhibition of Usp7 and Usp10 increased polyubiquitination of residual TAU inclusions.

Conclusions:

• Usp7 and Usp10 contribute to pathological TAU accumulation by influencing ubiquitin-dependent degradation pathways.
• Targeting Usp7 and Usp10 presents a potential novel therapeutic strategy for Alzheimer's disease and related tauopathies.
• Modulating DUB activity offers a promising avenue for developing treatments for neurodegenerative diseases characterized by protein aggregation.