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Schweighauser M, Shi Y, Tarutani A, Kametani F, Murzin AG, Ghetti B, Matsubara T, Tomita T, Ando T, Hasegawa K, Murayama S, Yoshida M, Hasegawa M, Scheres SH, Goedert M. Structures of α-synuclein filaments from multiple system atrophy. Nature. 2020 Sep;585(7825):464-469. Epub 2020 May 27 PubMed.
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Indiana University School of Medicine
Goedert’s group, including colleagues from Tokyo and Indiana, has made a seminal contribution to the field, and far beyond it. It is of particular note that “The three-dimensional structures look nothing like those formed by Aβ or tau fibrils, or indeed by fibrils made in the lab from recombinant α-synuclein.”
A common presumption we make is that recombinant protein samples, since they are “the same protein,” must behave like a native protein. This is a logical assumption. The authors, on the other hand, elegantly presented the first-ever cryo-electron microscopy of α-synuclein fibrils. Their paper revealed that their fundamental structure differed not only from tau or Aβ fibrils, which would not be unexpected, but that data amassed from recombinant α-synuclein is not reliable.
Our field is dominated by a reductionist hierarchism. Single mutations give rise to differences in protein or expression, which then give rise, in a yet unknown manner, to biochemical dysfunction, trivially leading to pathogenic bodies and diseases.
This group has once again demonstrated that emergent traits are often the rule in biology, where traits of a higher level of organization (structure) are not trivially deduced from the traits of a lower level. Or, indeed, even a simplified but “identical” (recombinant) example allegedly at the same hierarchical level does not trivially predict actual living behavior.
It is poetic that this larger-scale discovery was made using tools at some of the smallest scales (atomic-scale visualization). Passing the molecular baton to the atomic extent is joyful to watch. The precise twist and folding of protofibrillar structure are so consequential for brain and diseases (AD, PD, MSA). In a broad context, the finding is a historical leap.
Like neurodegenerative diseases, this finding evokes a parallel in how space exploration needs to be precise even at a large scale. We witnessed a successful docking of the SpaceX Dragon crew capsule at the International Space Station during the recent historic SpaceX/ NASA mission—what a convergence of astronaut and structural biologist of profound impact at very different levels!
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