KCTD10 p.C124W variant contributes to schizophrenia by attenuating LLPS-mediated synapse formation

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• KCTD10 is linked to neuropsychiatric disorders and acts within the ubiquitin ligase complex.
• A rare KCTD10 variant (p.C124W) found in schizophrenia cases lacks a clear pathogenic mechanism.
• Understanding KCTD10's role is crucial for elucidating brain disorder development.

Purpose of the Study:

• To investigate the pathogenic mechanism of the KCTD10 p.C124W variant.
• To explore the role of liquid-liquid phase separation (LLPS) in KCTD10 function and brain disorders.
• To identify potential therapeutic targets for KCTD10-associated conditions.

Main Methods:

• Generated heterozygous KCTD10 C124W mutant mice.
• Assessed synaptic structure and schizophrenia-like behaviors in mice.
• Investigated KCTD10's liquid-liquid phase separation (LLPS) properties and its interaction with RHOB.
• Analyzed RHOB levels in postsynaptic density fractions.

Main Results:

• KCTD10 C124W mice exhibited synaptic abnormalities and schizophrenia-like behaviors.
• KCTD10 undergoes LLPS via its intrinsically disordered region (IDR).
• The p.C124W mutation impaired KCTD10's LLPS, causing RHOB accumulation due to reduced degradation.
• Neither IDR deletion nor the p.C124W mutation rescued synaptic issues in Kctd10-deficient mice.

Conclusions:

• LLPS is implicated in the pathogenesis of KCTD10-associated brain disorders.
• Disruption of KCTD10 LLPS leads to synaptic dysfunction and behavioral deficits.
• RHOB accumulation is a key pathological event, suggesting RHOB as a therapeutic target for KCTD10-related diseases.