Tau filaments with the Alzheimer fold in cases with<i>MAPT</i>mutations V337M and R406W

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

doi:10.1101/2024.04.29.591661

Cited by 4 publications

References 72 publications

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Tau filaments with the chronic traumatic encephalopathy fold in a case of vacuolar tauopathy with VCP mutation D395G

Qi,

Kobayashi,

Kawakatsu

et al. 2024

Acta Neuropathol

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Dominantly inherited mutation D395G in the gene encoding valosin-containing protein causes vacuolar tauopathy, a type of behavioural-variant frontotemporal dementia, with marked vacuolation and abundant filamentous tau inclusions made of all six brain isoforms. Here we report that tau inclusions were concentrated in layers II/III of the frontotemporal cortex in a case of vacuolar tauopathy. By electron cryo-microscopy, tau filaments had the chronic traumatic encephalopathy (CTE) fold. Tau inclusions of vacuolar tauopathy share this cortical location and the tau fold with CTE, subacute sclerosing panencephalitis and amyotrophic lateral sclerosis/parkinsonism-dementia complex, which are believed to be environmentally induced. Vacuolar tauopathy is the first inherited disease with the CTE tau fold.

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Tau filaments with the chronic traumatic encephalopathy fold in a case of vacuolar tauopathy with VCP mutation D395G

Qi,

Kobayashi,

Kawakatsu

et al. 2024

Acta Neuropathol

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CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis

Samelson,

Ariqat,

McKetney

et al. 2023

Preprint

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A hallmark of age-associated neurodegenerative diseases is the aggregation of proteins. Aggregation of the protein tau defines tauopathies, which include Alzheimer's disease and frontotemporal dementia. Specific neuronal subtypes are selectively vulnerable to the accumulation of tau aggregates, and subsequent dysfunction and death. The mechanisms underlying cell type-selective vulnerability are unknown. To systematically uncover the cellular factors controlling the accumulation of tau aggregates in human neurons, we conducted a genome-wide CRISPRi-based modifier screen in iPSC-derived neurons. The screen uncovered expected pathways, including autophagy, but also unexpected pathways, including UFMylation and GPI anchor synthesis, that control tau oligomer levels. The E3 CUL5 ubiquitin ligase is a potent modifier of tau levels, and directly interacts with tau. Disruption of mitochondrial function increases tau oligomer levels and promotes proteasomal misprocessing of tau. These results reveal new principles of tau proteostasis in human neurons and pinpoint potential therapeutic targets for tauopathies.

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Novel tau filament folds in individuals withMAPTmutations P301L and P301T

Schweighauser,

Shi,

Murzin

et al. 2024

Preprint

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Mutations in MAPT, the microtubule-associated protein tau gene, give rise to cases of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) with abundant filamentous tau inclusions in brain cells. Individuals with pathological MAPT variants exhibit behavioural changes, cognitive impairment and signs of parkinsonism. Missense mutations of residue P301, which are the most common MAPT mutations associated with FTDP-17, give rise to the assembly of mutant four-repeat tau into filamentous inclusions, in the absence of extracellular deposits. Here we report the cryo-EM structures of tau filaments from five individuals belonging to three unrelated families with mutation P301L and from one individual belonging to a family with mutation P301T. A novel three-lobed tau fold resembling the two-layered tau fold of Pick's disease was present in all cases with the P301L tau mutation. Two different tau folds were found in the case with mutation P301T, the less abundant of which was a variant of the three-lobed fold. The major P301T tau fold was V-shaped, with partial similarity to the four-layered tau folds of corticobasal degeneration and argyrophilic grain disease. These findings suggest that FTDP-17 with mutations in P301 should be considered distinct inherited tauopathies and that model systems with these mutations should be used with caution in the study of sporadic tauopathies.

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Tau filaments with the Alzheimer fold in cases withMAPTmutations V337M and R406W

Cited by 4 publications

References 72 publications

Tau filaments with the chronic traumatic encephalopathy fold in a case of vacuolar tauopathy with VCP mutation D395G

Tau filaments with the chronic traumatic encephalopathy fold in a case of vacuolar tauopathy with VCP mutation D395G

CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis

Novel tau filament folds in individuals withMAPTmutations P301L and P301T

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