Bez, Sumi Lena; (2025) Investigating the contribution of an intronic variant at the TRIM11 locus to pathological and clinical heterogeneity in progressive supranuclear palsy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Progressive supranuclear palsy (PSP) is a primary 4R tauopathy characterised by pathological tau accumulation in neurons and glia. It manifests as nine distinct clinical phenotypes, complicating patient decline and prognosis predictions. An intronic variant in the TRIM11 gene was identified as a potential modifier of PSP phenotype and clinical diversity. TRIM11 has been implicated in tau regulation through SUMO E3 ligase, disaggregase, and molecular chaperone activities; however, its role in pathological tau processing as an E3 ubiquitin ligase remains unknown. This study aims to investigate how TRIM11 contributes to pathological tau clearance and to assess the functional relevance of the TRIM11 intronic variant. Using co-immunoprecipitation in HEK293T biosensors expressing full-length 1N4R tau with a P301S mutation and in vitro assays, TRIM11 was identified as a novel E3 ubiquitin ligase for tau, facilitating its proteasomal degradation. TRIM11 also acts as a molecular chaperone, effectively preventing tau fibril formation. To assess the ability of TRIM11 to prevent tau aggregation, TRIM11 levels were altered in a novel 4R induced pluripotent stem cell (iPSC)-derived model of tau pathology and in HEK293T tau biosensors expressing a P301S-mutated repeat domain. Overexpression of TRIM11 significantly reduced total and oligomeric tau levels and conferred protection against seeding insults. Novel hTauKI mutant tauopathy mouse models were then characterised and subsequently used to study whether TRIM11 overexpression can reduce and/or slow disease progression. TRIM11 overexpression reduced seed-competent tau in hTauKI P301S+3 mice and reversed AT8-positive tau pathology within 14 days in PS19 mouse brains. These findings position TRIM11 as a promising pharmacological target for the treatment of PSP and other tauopathies, where its overexpression could substantially mitigate tau pathology and disease progression.

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