Project Portugal 2030

Summary

HD early pathological mechanisms involve mitochondrial dysfunction and increased reactive oxygen species (ROS) generation. Likewise, Src kinase family (SKF) members, as Fyn, are regulated by ROS and influence mitochondrial function (e.g.Ogura et al., 2012). Furthermore, we recently showed decreased co-localization of c-Src/Fyn with mitochondria in several HD models, while expression of constitutive active c-Src/Fyn restored active SKF levels in striatal cells and in striatal neurons from YAC128 mice, improved mitochondrial morphology and function (Fão et al., 2023). These data raised a new hypothesis towards the contribution of abnormal Fyn-mitochondrial interactors in HD pathogenesis. Moreover, Fyn protein was shown to have an important role in synaptic GluN2B-composed NMDARs phosphorylation and activity, restoring CREB activation and decreasing caspase-3 levels, indicative of a decrease in cell death by apoptosis in HD (Fão et al., 2022). Thus, the current project aims to explore molecular dynamic analysis in in vitro and in vivo models to study how Fyn overexpression (FynOV) impacts the behavior and motor performance, striatal architecture and mitochondrial and synapse function in HD. Moreover, it will elucidate differential Fyn-mitochondrial protein interactors in HD mouse brain striatal mitochondria and isolated neurons, and determine whether Tyr-phospho mimetic forms of selective interactor mitochondrial proteins can ameliorate mitochondrial function in HD cells. Together, this project will provide the first evidence for the causal implication of Fyn in mitochondrial deregulation in HD pathogenesis.