8A9L

Cryo-EM structure of alpha-synuclein filaments from Parkinson's disease and dementia with Lewy bodies

Summary for 8A9L

• Entry DOI: 10.2210/pdb8a9l/pdb
• EMDB information: 15285
• Descriptor: Alpha-synuclein, Unknown fragment, ... (4 entities in total)
• Functional Keywords: alpha-synuclein, amyloid, fibril, parkinson's disease (pd), parkinson's disease dementia (pdd), dementia with lewy bodies (dlb), synucleinopathy, protein fibril
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 15887.84

Authors

Yang, Y.,Shi, Y.,Schweighauser, M.,Zhang, X.J.,Kotecha, A.,Murzin, A.G.,Garringer, H.J.,Cullinane, P.,Saito, Y.,Foroud, T.,Warner, T.T.,Hasegawa, K.,Vidal, R.,Murayama, S.,Revesz, T.,Ghetti, B.,Hasegawa, M.,Lashley, T.,Scheres, H.W.S.,Goedert, M. (deposition date: 2022-06-28, release date: 2022-08-31, Last modification date: 2024-07-24)

Primary citation

Yang, Y.,Shi, Y.,Schweighauser, M.,Zhang, X.,Kotecha, A.,Murzin, A.G.,Garringer, H.J.,Cullinane, P.W.,Saito, Y.,Foroud, T.,Warner, T.T.,Hasegawa, K.,Vidal, R.,Murayama, S.,Revesz, T.,Ghetti, B.,Hasegawa, M.,Lashley, T.,Scheres, S.H.W.,Goedert, M.
Structures of alpha-synuclein filaments from human brains with Lewy pathology.
Nature, 610:791-795, 2022

PubMed Abstract: Parkinson's disease (PD) is the most common movement disorder, with resting tremor, rigidity, bradykinesia and postural instability being major symptoms. 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 nigra. 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 diagnosis. 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 onset. In PDD, cognitive impairment develops in the setting of well-established PD. Besides PD and DLB, multiple system atrophy (MSA) is the third major synucleinopathy. 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 MSA. 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.

PubMed: 36108674
DOI: 10.1038/s41586-022-05319-3

Experimental method

ELECTRON MICROSCOPY (2.2 Å)