Structures of α-synuclein filaments from human brains with Lewy pathology

Yang Yang, Yang Shi, Manuel Schweighauser, Xianjun Zhang, Abhay Kotecha, Alexey G. Murzin, Holly J. Garringer, Patrick W. Cullinane, Yuko Saito, Tatiana Foroud, Thomas T. Warner, Kazuko Hasegawa, Ruben Vidal, Shigeo Murayama, Tamas Revesz, Bernardino Ghetti, Masato Hasegawa, Tammaryn Lashley, Sjors H. W. Scheres () and Michel Goedert ()
Additional contact information
Yang Yang: Medical Research Council Laboratory of Molecular Biology
Yang Shi: Medical Research Council Laboratory of Molecular Biology
Manuel Schweighauser: Medical Research Council Laboratory of Molecular Biology
Xianjun Zhang: Thermo Fisher Scientific
Abhay Kotecha: Thermo Fisher Scientific
Alexey G. Murzin: Medical Research Council Laboratory of Molecular Biology
Holly J. Garringer: Indiana University School of Medicine
Patrick W. Cullinane: University College London
Yuko Saito: Metropolitan Institute of Gerontology
Tatiana Foroud: Indiana University School of Medicine
Thomas T. Warner: University College London
Kazuko Hasegawa: Sagamihara National Hospital
Ruben Vidal: Indiana University School of Medicine
Shigeo Murayama: University of Osaka
Tamas Revesz: University College London
Bernardino Ghetti: Indiana University School of Medicine
Masato Hasegawa: Metropolitan Institute of Medical Science
Tammaryn Lashley: University College London
Sjors H. W. Scheres: Medical Research Council Laboratory of Molecular Biology
Michel Goedert: Medical Research Council Laboratory of Molecular Biology

Nature, 2022, vol. 610, issue 7933, 791-795

Abstract: Abstract Parkinson’s disease (PD) is the most common movement disorder, with resting tremor, rigidity, bradykinesia and postural instability being major symptoms1. Neuropathologically, it is characterized by the presence of abundant filamentous inclusions of α-synuclein in the form of Lewy bodies and Lewy neurites in some brain cells, including dopaminergic nerve cells of the substantia nigra2. PD is increasingly recognised as a multisystem disorder, with cognitive decline being one of its most common non-motor symptoms. Many patients with PD develop dementia more than 10 years after diagnosis3. PD dementia (PDD) is clinically and neuropathologically similar to dementia with Lewy bodies (DLB), which is diagnosed when cognitive impairment precedes parkinsonian motor signs or begins within one year from their onset4. In PDD, cognitive impairment develops in the setting of well-established PD. Besides PD and DLB, multiple system atrophy (MSA) is the third major synucleinopathy5. It is characterized by the presence of abundant filamentous α-synuclein inclusions in brain cells, especially oligodendrocytes (Papp-Lantos bodies). We previously reported the electron cryo-microscopy structures of two types of α-synuclein filament extracted from the brains of individuals with MSA6. Each filament type is made of two different protofilaments. Here we report that the cryo-electron microscopy structures of α-synuclein filaments from the brains of individuals with PD, PDD and DLB are made of a single protofilament (Lewy fold) that is markedly different from the protofilaments of MSA. These findings establish the existence of distinct molecular conformers of assembled α-synuclein in neurodegenerative disease.

Date: 2022
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DOI: 10.1038/s41586-022-05319-3

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