In situ architecture of neuronal alpha-Synuclein inclusions

Trinkaus, V. A.; Riera-Tur, I.; Martinez-Sanchez, A.; Baeuerlein, F. J. B.; Guo, Q.; Arzberger, T.; Baumeister, W.; Dudanova, I.; Hipp, M. S.; Hartl, F. U.; Fernandez-Busnadiego, R.

doi:10.1101/2020.08.07.234138

bioRxiv · 10.1101/2020.08.07.234138

In situ architecture of neuronal alpha-Synuclein inclusions

Trinkaus, V. A.·Riera-Tur, I.·Martinez-Sanchez, A.·Baeuerlein, F. J. B.·Guo, Q.·Arzberger, T.·Baumeister, W.·Dudanova, I.·Hipp, M. S.·Hartl, F. U.·Fernandez-Busnadiego, R.

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Abstract

-Synuclein (-Syn) aggregation is a hallmark of devastating neurodegenerative disorders including Parkinsons disease (PD) and multiple systems atrophy (MSA)1,2. -Syn aggregates spread throughout the brain during disease progression2, suggesting mechanisms of intercellular seeding. Formation of -Syn amyloid fibrils is observed in vitro3,4 and fibrillar -Syn has been purified from patient brains5,6, but recent reports questioned whether disease-relevant -Syn aggregates are fibrillar in structure7-9. Here we use cryo-electron tomography (cryo-ET) to image neuronal Lewy body-like -Syn inclusions in situ at molecular resolution. We show that the inclusions consist of -Syn fibrils crisscrossing a variety of cellular organelles such as the endoplasmic reticulum (ER), mitochondria and autophagic structures, without interacting with membranes directly. Neuronal inclusions seeded by recombinant or MSA patient-derived -Syn aggregates have overall similar architecture, although MSA-seeded fibrils show higher structural flexibility. Using gold-labeled seeds we find that aggregate nucleation is predominantly mediated by -Syn oligomers, with fibrils growing unidirectionally from the seed. Our results conclusively demonstrate that neuronal -Syn inclusions contain -Syn fibrils intermixed with cellular membranes, and illuminate the mechanism of aggregate nucleation.

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Trinkaus, V. A., Riera-Tur, I., Martinez-Sanchez, A., Baeuerlein, F. J. B., Guo, Q., Arzberger, T., Baumeister, W., Dudanova, I., Hipp, M. S., Hartl, F. U., Fernandez-Busnadiego, R.. 2020-08-07. In situ architecture of neuronal alpha-Synuclein inclusions. https://doi.org/10.1101/2020.08.07.234138

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