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Two New Polymorphs in H50Q Determined by CryoEM Suggest a Mechanism That Explains Its Faster Kinetics In Vitro

To understand the mechanisms underlying the formation of α-synuclein (αSyn) fibrils in the brain, it is crucial to establish a connection between amyloid structure and the molecular interactions that trigger the development of diseases in patients. Evidence of this connection has been reported for the G51D mutations, in which a relationship between the levels of β-sheet structure and neurotoxicity was observed. Furthermore, an exceptional progress was achieved with the determination of the Cryo-EM structure of in vitro created WT αSyn fibrils, revealing 2 morphologies: a rod-like and a twister polymorph, both composed of 2 protofilaments that share a kernel structure at the N-terminal domain, but a different position of the interface between protofilaments. To provide more elements that strengthen the link between fibril structure and disease, Boyer and colleagues determined the Cryo-EM structure of H50Q and E46K mutations. For H50Q, an additional network of hydrogen bonds at the N-terminal domain, promoted by the mutation, led not just to the displacement of the interfacial region, but also conferred stability to the fibril as a single protofilament, probably leading to faster nucleation. For the E46K mutation, the doubleprotofilament fibril shows drastic modification in the kernel structure because of a repulsive interaction between the E46K and K80 mutations, which force a new arrangement at the protofilament interface to diminish the energetic penalization of the positively charged residues and concomitantly unlock a more stable fibril. These findings are part of an emerging body of evidence in which the accumulation of atomic-level structure of amyloid fibril knowledge will make it possible to understand how punctual changes can generate the clinal onsets observed in patients. The structural data obtained for the H50Q mutation offers an explanation of its faster kinetics in vitro; however, this information by itself is not enough to elucidate how the mutation affects the interaction of mature fibrils and oligomers with other key elements in the cell, like relevant molecules, proteins, or organelles, events that could ultimately explain the increased severity of phenotypes in patients. This point has been addressed for the case of E46K, in which stronger fibril interactions with mitochondrial peptides are believed to confer greater cytotoxicity. With the atomic structure of the aSyn fibrils as a framework, further investigation is required to explore specific interactions with distinctive molecules present in different regions of the brain. This knowledge would allow a better molecular comprehension of the development of synucleinopathies in patients.