Browsing by Author "Cullinane, Patrick W."

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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.
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    Tau filaments with the Alzheimer fold in cases with MAPT mutations V337M and R406W
    (bioRxiv, 2024-04-30) Qi, Chao; Lövestam, Sofia; Murzin, Alexey G.; Peak-Chew, Sew; Franco, Catarina; Bogdani, Marika; Latimer, Caitlin; Murrell, Jill R.; Cullinane, Patrick W.; Jaunmuktane, Zane; Bird, Thomas D.; Ghetti, Bernardino; Scheres, Sjors H. W.; Goedert, Michel; Pathology and Laboratory Medicine, School of Medicine
    Frontotemporal dementia (FTD) and Alzheimer's disease are the most common forms of early-onset dementia. Dominantly inherited mutations in MAPT, the microtubule-associated protein tau gene, cause FTD and parkinsonism linked to chromosome 17 (FTDP-17). Individuals with FTDP-17 develop abundant filamentous tau inclusions in brain cells. Here we used electron cryo-microscopy to determine the structures of tau filaments from the brains of individuals with MAPT mutations V337M and R406W. Both mutations gave rise to tau filaments with the Alzheimer fold, which consisted of paired helical filaments in all V337M and R406W cases and of straight filaments in two V337M cases. We also identified a new assembly of the Alzheimer fold into triple tau filaments in a V337M case. Filaments assembled from recombinant tau(297-391) with mutation V337M had the Alzheimer fold and showed an increased rate of assembly.