Sandra de Macedo Ribeiro
University of Porto, Portugal

Sandra de Macedo Ribeiro graduated in Biochemistry at the University of Porto, Portugal, in 1992 and completed her Ph.D. at the Technical University of Munich, Germany, in 1999. Her training in Protein Crystallography started in 1992 as an Erasmus student at the University of Aarhus, Denmark, and proceeded under the supervision of Prof. Ana Margarida Damas, University of Porto,  where she worked on the crystallization and structural characterization on transthyretin (TTR) mutants. Sandra’s Ph.D. research, under the supervision of Prof. Robert Huber at Max-Planck-Institut für Biochemie, Martinsried, Germany, focused on the structural analysis of the determinants of protein thermostability in ferredoxins, and on the determination of the structural features linked with calcium-independent membrane association of the membrane-binding C2 domain of coagulation factor V. During her postdoctoral research training with Prof. Miquel Coll, CSIC, Barcelona, Spain, Sandra contributed for the elucidation of the ligand binding specificity of human biliverdin IX-β reductase, a major heme catabolic enzyme during early fetal development.

In 2001, Sandra moved to the University of Algarve, Portugal, as a Lecturer in Biochemistry, and in 2003 to the Center of Neuroscience and Cell Biology, Coimbra, Portugal, where she led the Protein Structure Group. Sandra’s research then started to focus on the structural and functional analysis of ataxin-3, a polyglutamine-rich protein associated with Machado-Joseph disease, a neurodegenerative disorder with high prevalence in Portugal. In 2006, Sandra joined the Institute for Molecular and Cellular Biology, Porto, Portugal, where she currently leads the Protein Crystallography Group, and the Biomolecular Structure and Function Group of the recently formed i3S Research Consortium. Research in Sandra de Macedo Ribeiro’s lab focuses on the structural and functional characterization of biomedically relevant proteins, with a special emphasis on understanding the modulatory role of intermolecular interactions on proteins associated with cell signaling and neurodegenerative diseases.

Ataxin-3 aggregation: The determinant role of polyglutamine-independent features in the earliest amyloid fibril formation steps

The expansion of a trinucleotide (CAG) repeat, translated into a polyglutamine expanded sequence in the protein encoded by the MJD gene, was identified over 20 years ago as the causative mutation in a severe neurodegenerative disorder originally diagnosed in individuals of Portuguese ancestry. Machado-Joseph disease (MJD), or spinocebellar ataxia type 3 (SCA3), is caused by extension of a CAG repeat in the gene coding for ataxin-3, a protein with ubiquitin hydrolase activity. Although polyglutamine expansion is an obvious trigger for neuronal dysfunction, different domains of this multidomain protein play a role in the function and aggregation properties of ataxin-3.

Ataxin-3 is a modular protein, with a globular N-terminal domain (Josephin domain, JD), a flexible C-terminal tail containing ubiquitin interaction motifs, and a polyglutamine(polyQ)-rich region. The JD has a number of aggregation-prone regions, playing a central role in the early aggregation steps of both normal and polyQ-expanded ataxin-3. Small oligomers and protofibrils from non-pathological ataxin-3 and JD are efficiently detected by a specific antibody, which universally recognizes toxic amyloid oligomeric structures from unrelated amyloid-forming proteins (Figure 1). These findings suggest that studying the “slower” aggregation pathway of normal ataxin-3 or of the JD will provide clues to identify early intermediates with relevance for neuronal degeneration and for identifying assembly inhibitors with potential therapeutic applications. The Ribeiro research team is currently studying small molecules and proteins with the ability to modify the ataxin-3 aggregation pathway.

Figure 1. Self-assembly of non-pathological ataxin-3 into amyloid-like protofibrils as shown by transmission electron microscopy. These structures can be recognized by the anti-oligomer antibody, A11, which generally binds to cytotoxic oligomers formed by different amyloidogenic proteins. The structure of the globular Josephin domain is shown in blue with the aggregation-prone region colored in yellow.

The Biomolecular Structure and Function research group from IBMC/i3S, Porto, Portugal.