VCP regulates early tau seed amplification via specific cofactors

Area of Science:

• Neurobiology
• Cell Biology
• Biochemistry

Background:

• Neurodegenerative tauopathies may progress via templated seeding of pathological tau assemblies.
• Cell-to-cell transmission of tau aggregates initiates replication in the cytoplasm within hours.
• Unknown factors likely regulate this rapid seeding process.

Purpose of the Study:

• To identify proteins regulating tau seed amplification using proximity labeling.
• To investigate the mechanistic role of Valosin containing protein (VCP/p97) in tau seeding.

Main Methods:

• Proximity labeling with split-APEX2 fused to tau repeat domain (RD) to identify VCP/p97.
• Utilized immortalized cells and human neurons to study VCP effects on tau seeding.
• Assessed tau aggregation following genetic and pharmacological VCP manipulation.

Main Results:

• VCP knockdown significantly reduced tau seeding.
• Chemical inhibitors showed opposing effects on seeding, with timing crucial (within 8h).
• Co-factor screening identified ATXN3, NSFL1C, UBE4B, NGLY1, OTUB1, and NPLOC4 as inhibitors of seeding, while FAF2 enhanced it.

Conclusions:

• VCP acts as a central regulator of tau seeding, influencing early processing.
• Divergent effects of inhibitors and co-factor modulation highlight VCP's complex role.
• A cytoplasmic VCP-centered complex may direct tau seeds towards degradation or amplification.