D-023 | UNVEILING THE ROLE OF PIAS4 AS A KEY PLAYER IN TAU PATHOLOGICAL ACCUMULATION

Cellular and Molecular Neurobiology
Author: María Clara Sokn | Email: sokn.maria@maimonides.edu

María Clara Sokn^1°4°, Facundo Claverie^1°4°, Camila Mimura^2°4°,  Victoria Ambrosino^3°, Angel Ramón Torres Mc Cook^1°, Gerson Smith Asti Tello^1°, Vanina Giselle Velardo^1°,  Ana Liberman^1°2°

^1° Centro de Estudios Biomédicos, Básicos, Aplicados y Desarrollo (CEBBAD), Universidad Maimónides (UMAI), Buenos Aires, Argentina.
^2° Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales (FCEyN), Universidad de Buenos Aires (UBA), Ciudad Universitaria, Buenos Aires, Argentina.
^3° Universidad Nacional de Quilmes, Buenos Aires, Argentina.
^4° Equally contributed

Tauopathies are neurodegenerative diseases characterized by aberrant tau protein homeostasis. Given the role of PIAS SUMO ligases in the regulation of neurodegeneration-related proteins, this study examined their impact on tau regulation.
A Western Blot screen in HT22 cells overexpressing wild-type (WT) human 2N4R tau (hTau) alongside PIAS family members revealed that PIAS4 overexpression significantly increased total tau levels. In addition, bimolecular fluorescence complementation (BiFC) analysis showed that PIAS4 promotes tau dimerization, a critical step in pathological aggregation.
To corroborate these findings, N2a cells stably expressing endogenous levels of WT or a SUMOylation-deficient tau (hTauK340R) were utilized. PIAS4 enhanced the accumulation of both tau forms, suggesting a tau SUMOylation-independent mechanism of action. Nickel purification assays confirmed the inability of PIAS4 to induce tau SUMO conjugation.
Furthermore, PIAS4 knockdown using two distinct shRNA vectors resulted in a significant reduction of total tau protein levels, implying a role for PIAS4 in regulating tau degradation. To explore the potential involvement of autophagy in this process, the impact of PIAS4 modulation on autophagic flux was examined. Overexpression of PIAS4 inhibited autophagy, while its knockdown enhanced this cellular clearance mechanism.
Collectively, these findings position PIAS4 as a key regulator of tau homeostasis.