I'm a PhD student at ICVS, and my PhD project aims to clarify the role of neurospecificity in the Machado-Joseph Disease (MJD). MJD is a late-onset neurodegenerative disorder, caused by a polyglutamine (polyQ)expansion in ataxin-3 and affecting specific brain regions. The mutant ataxin-3 shows a strong tendency to misfold and aggregate leading to the formation of neuronal inclusions, hallmarks of pathology. Knowing that both normal andmutant ataxin-3 are ubiquitously expressed throughout the brain and differences in ataxin-3 aggregation fail to correlate with ataxin-3 tissue/neuron-specific expression levels or heterogeneity of polyQ-length, we pose a challenging question: what causes the neuron-specific pattern of degeneration underlying MJD? To address this question we will use a transgenic C. elegans model mimicking important features of the disease. We expect to provide new insights into common and protein-specific mechanisms of aggregation and selective neurodegeration in MJD and other polyQ diseases, opening new pathways for development of therapeutic strategies.
Teixeira-Castro A*, Jalles AL*, Esteves S*, Kang S, Santos L, Silva-Fernandes A, Neto M, Brielmann RM, Bessa C, Miranda A, Oliveira S, Neves-Carvalho A, Bessa J, Summavielle T, Silvermann RB, Oliveira P, Morimoto RI, Maciel P. Serotonergic signaling suppresses ataxin-3 aggregation and neurotoxicity in animal models of Machado-Joseph disease. Brain, 138(Pt 11):3221-3237 (2015).