Variation at the TRIM11 locus modifies progressive supranuclear palsy phenotype.

Area of Science:

• Neurogenetics
• Neurobiology

Background:

• Clinical variability in progressive supranuclear palsy (PSP) lacks a clear genetic explanation.
• Understanding the genetic underpinnings of PSP phenotypes is crucial for developing targeted therapies.

Purpose of the Study:

• To identify genetic factors influencing the clinical presentation of progressive supranuclear palsy (PSP) through a genome-wide association study (GWAS).

Main Methods:

• Genome-wide association studies (GWAS) were conducted on two independent PSP cohorts, comparing Richardson syndrome (RS) and non-RS groups.
• Analysis included logistic regression, combined cohort analysis, validation in a third cohort, and assessment of gene expression patterns.
• Gene-based association testing was performed to confirm findings at the TRIM11 locus.

Main Results:

• A significant association was found with single nucleotide polymorphism (SNP) rs564309, located within the TRIM11 gene, reaching genome-wide significance (p = 1.7 × 10⁻⁹).
• TRIM11, a component of the ubiquitin proteasome system (UPS), is predominantly expressed in neurons within the cerebellum and basal ganglia.
• Replication in a third cohort and gene-based association testing confirmed the role of TRIM11 in PSP.

Conclusions:

• The TRIM11 locus acts as a genetic modifier of PSP phenotype.
• These findings provide further support for the involvement of the ubiquitin proteasome system (UPS) in tau pathology and suggest TRIM11 as a potential target for disease-modifying therapies for PSP.