S-003 | How do Tau mutations alter mitochondrial dynamics and fuel neurodegeneration?

Cellular and Molecular Neurobiology
Author: Julieta Bianchelli | Email: juli.bianchelli@gmail.com

Julieta Bianchelli^1°, Mariana Holubiec^1°2°, Cayetana Arnaiz^1°,  Jordi Navarro^2°, Tomás Falzone^1°2°

^1° Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) – CONICET – Partner Institute of the Max Planck Society
^2° Instituto de Biología Celular y Neurociencias (IBCN) “Profesor Eduardo De Robertis” – CONICET – UBA

Tau, a microtubule-associated protein, plays crucial roles in axonal transport. Tau mutations lead to its phosphorylation, disrupting mitochondrial transport and generating oxidative stress in the neurodegeneration process. The V337M tau mutation has been linked to frontotemporal dementia, in which cortical glutamatergic neurons are significantly affected. Therefore, to understand how tau V337M affects mitochondrial homeostasis and dynamics, we stablished a pharmacological differentiation protocol to obtain human glutamatergic neurons from mutant and isogenic hiPSCs. Axonal transport dynamics in vehicle and oxidized conditions, induced by Paraquat (PQ), were studied. PQ reduced axonal mitochondrial density and increased the segmental velocities (SVs) distributions in control neurons. However, we found a decrease in retrograde SVs both in vehicle and PQ treated V337M neurons. Moreover, mitochondria from mutant neurons exhibited reduced lengths than isogenic controls, a difference that increased after PQ treatment. In addition, we generated genetically induced glutamatergic neurons (i3N) to assess their redox state, observing higher mitochondrial depolarization in V337M i3N compared to controls, an effect that was increased after PQ. Immunofluorescent staining in i3N against phospho-tau will uncover differences in its axonal distribution. Moreover, mitochondrial redox state and transport will be evaluated in glutamatergic derived brain organoids from mutant and isogenic hiPSCs.