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Structure of the toxic core of ?-synuclein from invisible crystals.

ABSTRACT: The protein ?-synuclein is the main component of Lewy bodies, the neuron-associated aggregates seen in Parkinson disease and other neurodegenerative pathologies. An 11-residue segment, which we term NACore, appears to be responsible for amyloid formation and cytotoxicity of human ?-synuclein. Here we describe crystals of NACore that have dimensions smaller than the wavelength of visible light and thus are invisible by optical microscopy. As the crystals are thousands of times too small for structure determination by synchrotron X-ray diffraction, we use micro-electron diffraction to determine the structure at atomic resolution. The 1.4 Å resolution structure demonstrates that this method can determine previously unknown protein structures and here yields, to our knowledge, the highest resolution achieved by any cryo-electron microscopy method to date. The structure exhibits protofibrils built of pairs of face-to-face ?-sheets. X-ray fibre diffraction patterns show the similarity of NACore to toxic fibrils of full-length ?-synuclein. The NACore structure, together with that of a second segment, inspires a model for most of the ordered portion of the toxic, full-length ?-synuclein fibril, presenting opportunities for the design of inhibitors of ?-synuclein fibrils.

SUBMITTER: Rodriguez JA

PROVIDER: S-EPMC4791177 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Structure of the toxic core of α-synuclein from invisible crystals.

Rodriguez Jose A JA Ivanova Magdalena I MI Sawaya Michael R MR Cascio Duilio D Reyes Francis E FE Shi Dan D Sangwan Smriti S Guenther Elizabeth L EL Johnson Lisa M LM Zhang Meng M Jiang Lin L Arbing Mark A MA Nannenga Brent L BL Hattne Johan J Whitelegge Julian J Brewster Aaron S AS Messerschmidt Marc M Boutet Sébastien S Sauter Nicholas K NK Gonen Tamir T Eisenberg David S DS

Nature 20150909 7570

The protein α-synuclein is the main component of Lewy bodies, the neuron-associated aggregates seen in Parkinson disease and other neurodegenerative pathologies. An 11-residue segment, which we term NACore, appears to be responsible for amyloid formation and cytotoxicity of human α-synuclein. Here we describe crystals of NACore that have dimensions smaller than the wavelength of visible light and thus are invisible by optical microscopy. As the crystals are thousands of times too small for struc ...[more]

PMID: 26352473

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Project description:Parkinson's Disease (PD) is a neurodegenerative and progressive disorder characterised by intracytoplasmic inclusions called Lewy bodies (LB) and degeneration of dopaminergic neurons in the substantia nigra (SN). Aggregated α-synuclein (αSYN) is known to be the main component of the LB. It has also been reported to interact with several proteins and organelles. Galectin-3 (GAL3) is known to have a detrimental function in neurodegenerative diseases. It is a galactose-binding protein without known catalytic activity and is expressed mainly by activated microglial cells in the central nervous system (CNS). GAL3 has been previously found in the outer layer of the LB in post-mortem brains. However, the role of GAL3 in PD is yet to be elucidated. In post-mortem samples, we identified an association between GAL3 and LB in all the PD subjects studied. GAL3 was linked to less αSYN in the LB outer layer and other αSYN deposits, including pale bodies. GAL3 was also associated with disrupted lysosomes. In vitro studies demonstrate that exogenous recombinant Gal3 is internalised by neuronal cell lines and primary neurons where it interacts with endogenous αSyn fibrils. In addition, aggregation experiments show that Gal3 affects spatial propagation and the stability of pre-formed αSyn fibrils resulting in short, amorphous toxic strains. To further investigate these observations in vivo, we take advantage of WT and Gal3KO mice subjected to intranigral injection of adenovirus overexpressing human αSyn as a PD model. In line with our in vitro studies, under these conditions, genetic deletion of GAL3 leads to increased intracellular αSyn accumulation within dopaminergic neurons and remarkably preserved dopaminergic integrity and motor function. Overall, our data suggest a prominent role for GAL3 in the aggregation process of αSYN and LB formation, leading to the production of short species to the detriment of larger strains which triggers neuronal degeneration in a mouse model of PD.

Dataset Information

Structure of the toxic core of ?-synuclein from invisible crystals.

Publications

Structure of the toxic core of α-synuclein from invisible crystals.

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