Browsing by Subject "Brain chemistry"

Now showing 1 - 4 of 4
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    Cryo-EM structures of amyloid-β 42 filaments from human brains
    (American Association for the Advancement of Science, 2022) Yang, Yang; Arseni, Diana; Zhang, Wenjuan; Huang, Melissa; Lövestam, Sofia; Schweighauser, Manuel; Kotecha, Abhay; Murzin, Alexey G.; Peak-Chew, Sew Y.; Macdonald, Jennifer; Lavenir, Isabelle; Garringer, Holly J.; Gelpi, Ellen; Newell, Kathy L.; Kovacs, Gabor G.; Vidal, Ruben; Ghetti, Bernardino; Falcon, Benjamin; Scheres, Sjors H.W.; Goedert, Michel; Pathology and Laboratory Medicine, School of Medicine
    Filament assembly of amyloid-β peptides ending at residue 42 (Aβ42) is a central event in Alzheimer’s disease. Here, we report the cryo–electron microscopy (cryo-EM) structures of Aβ42 filaments from human brains. Two structurally related S-shaped protofilament folds give rise to two types of filaments. Type I filaments were found mostly in the brains of individuals with sporadic Alzheimer’s disease, and type II filaments were found in individuals with familial Alzheimer’s disease and other conditions. The structures of Aβ42 filaments from the brain differ from those of filaments assembled in vitro. By contrast, in AppNL-F knock-in mice, Aβ42 deposits were made of type II filaments. Knowledge of Aβ42 filament structures from human brains may lead to the development of inhibitors of assembly and improved imaging agents.
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    Structures of α-synuclein filaments from human brains with Lewy pathology
    (Springer Nature, 2022) Yang, Yang; Shi, Yang; Schweighauser, Manuel; Zhang, Xianjun; Kotecha, Abhay; Murzin, Alexey G.; Garringer, Holly J.; Cullinane, Patrick W.; Saito, Yuko; Foroud, Tatiana; Warner, Thomas T.; Hasegawa, Kazuko; Vidal, Ruben; Murayama, Shigeo; Revesz, Tamas; Ghetti, Bernardino; Hasegawa, Masato; Lashley, Tammaryn; Scheres, Sjors H.W.; Goedert, Michel; Pathology and Laboratory Medicine, School of Medicine
    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.