Abstract 1395 Glycine-N-methyltransferase is not necessary for age-dependent Drosophila photoreceptor survival

Frontotemporal dementia (FTD) is a major early-onset neurodegenerative disease and the second most common dementia.FTD is characterized by distinct clinical syndromes and pathological hallmarks including Tau or TDP-43 protein dysregulation, and can also be caused by genetic mutations in either Tau or TDP-43.However, how Tau and TDP-43 mutations converge mechanistically in FTD still remains elusive.In this study, we identified a novel mechanistic convergence of FTD disease-associated mutations in both tau and TDP-43 on STIM1, a critical endoplasmic reticulum (ER) calcium sensor that regulates store-operated calcium entry.Using live Super-Resolution Lattice SIM2 microscopy of STIM1 dynamics, we demonstrated that TDP-43 disease-associated mutations result in STIM1 translocation to ER-plasma membrane contact sites.Similarly, Tau disease-associated mutations also result in Stim1 translocation to ER-plasma membrane contact sites.We further found that this may be mediated by the phosphorylation status of STIM1 at a key phosphosite, which plays a crucial role in its dynamic localization on the ER.These findings identify STIM1 dysregulation as a potential converging pathway in FTD, offering insights into the overlapping molecular mechanisms of Tau and TDP-43 pathology in neurodegeneration.