Alpha-synuclein (αSyn) is a highly expressed and conserved protein, typically found in the presynaptic terminals of neurons. The misfolding and aggregation of αSyn into amyloid fibrils is a pathogenic hallmark of several neurodegenerative diseases called synucleinopathies, such as Parkinson’s disease. Since αSyn is an Intrinsically Disordered Protein, the characterization of its structure remains very challenging. Moreover, the mechanisms by which the structural conversion of monomeric αSyn into oligomers and finally into fibrils takes place is still far to be completely understood. Over the years, various studies have provided insights into the possible pathways that αSyn could follow to misfold and acquire oligomeric and fibrillar forms. In addition, it has been observed that αSyn structure can be influenced by different parameters, such as mutations in its sequence, the biological environment (e.g., lipids, endogenous small molecules and proteins), the interaction with exogenous compounds (e.g., drugs, diet components, heavy metals). Herein, we review the structural features of αSyn (wild-type and disease-mutated) that have been elucidated up to present by both experimental and computational techniques in different environmental and biological conditions. We believe that this gathering of current knowledge will further facilitate studies on αSyn, helping the planning of future experiments on the interactions of this protein with targeting molecules especially taking into consideration the environmental conditions.

Tau is a protein characterized by large structural portions displaying extended conformational changes. Unfortunately, the accumulation of this protein into toxic aggregates in neuronal cells leads to a number of severe pathologies, collectively named tauopathies. In the last decade, significant research advancements were achieved, including a better understanding of Tau structures and their implication in different tauopathies. Interestingly, Tau is characterized by a high structural variability depending on the type of disease, the crystallization conditions, and the formation of pathologic aggregates obtained from in vitro versus ex vivo samples. In this review, we reported an up-to-date and comprehensive overview of Tau structures reported in the Protein Data Bank, with a special focus on discussing the connections between structural features, different tauopathies, different crystallization conditions, and the use of in vitro or ex vivo samples. The information reported in this article highlights very interesting links between all these aspects, which we believe may be of particular relevance for a more informed structure-based design of compounds able to modulate Tau aggregation.