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TitleIn situ architecture of neuronal α-Synuclein inclusions.
Journal, issue, pagesNat Commun, Vol. 12, Issue 1, Page 2110, Year 2021
Publish dateApr 14, 2021
AuthorsVictoria A Trinkaus / Irene Riera-Tur / Antonio Martínez-Sánchez / Felix J B Bäuerlein / Qiang Guo / Thomas Arzberger / Wolfgang Baumeister / Irina Dudanova / Mark S Hipp / F Ulrich Hartl / Rubén Fernández-Busnadiego /
PubMed AbstractThe molecular architecture of α-Synuclein (α-Syn) inclusions, pathognomonic of various neurodegenerative disorders, remains unclear. α-Syn inclusions were long thought to consist mainly of α-Syn ...The molecular architecture of α-Synuclein (α-Syn) inclusions, pathognomonic of various neurodegenerative disorders, remains unclear. α-Syn inclusions were long thought to consist mainly of α-Syn fibrils, but recent reports pointed to intracellular membranes as the major inclusion component. Here, we use cryo-electron tomography (cryo-ET) to image neuronal α-Syn inclusions in situ at molecular resolution. We show that inclusions seeded by α-Syn aggregates produced recombinantly or purified from patient brain consist of α-Syn fibrils crisscrossing a variety of cellular organelles. Using gold-labeled seeds, we find that aggregate seeding is predominantly mediated by small α-Syn fibrils, from which cytoplasmic fibrils grow unidirectionally. Detailed analysis of membrane interactions revealed that α-Syn fibrils do not contact membranes directly, and that α-Syn does not drive membrane clustering. Altogether, we conclusively demonstrate that neuronal α-Syn inclusions consist of α-Syn fibrils intermixed with membranous organelles, and illuminate the mechanism of aggregate seeding and cellular interaction.
External linksNat Commun / PubMed:33854052 / PubMed Central
MethodsEM (tomography)
Structure data

EMDB-11401:
Tomogram of GFP-a-synuclein inclusion in primary mouse neuron expressing GFP-a-synuclein, seeded with PFFs
Method: EM (tomography)

EMDB-11416:
Tomogram of GFP-a-synuclein inclusion in primary mouse neuron expressing GFP-a-synuclein, seeded with MSA aggregates
Method: EM (tomography)

EMDB-11417:
Tomogram of endogenous a-synuclein inclusion in primary mouse neurons seeded with PFFs
Method: EM (tomography)

Source
  • Mus musculus (house mouse)

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