Cryo-EM structures of tau filaments from Alzheimer’s disease

Fitzpatrick, Anthony; Falcon, Benjamin; He, Shaoda; Murzin, Alexey G.; Murshudov, Garib N.; Garringer, Holly J.; Crowther, R. Anthony; Ghetti, Bernardino; Goedert, Michel; Scheres, Sjors H.W.

doi:10.1038/nature23002

Cited by 1,563 publications

(2,118 citation statements)

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“…Indeed, recent cryoelectron microscopy data on fibrillar tau isolated from a patient with Alzheimer's disease (71) and previous structural NMR findings of tau (72) indicate that the PHF6 site is within a critical β-sheet stretch for amyloid folding needed to generate the core of paired helical filaments and straight filaments. Therefore, the impact of additional FTDP-17 associated mutations located near the PHF6 site-P301T, G303V, G304S, and S305N-were investigated.…”

Section: Discussionmentioning

confidence: 99%

“…Alternatively, cryo-electron microscopy data (71) indicates that, in tau fibrils, S320 is folded within a hydrophobic pocket, and thus the S320F mutation would strongly stabilize tau amyloid fold and subsequent fibril polymerization. Coupled with the paucity of the proline at residue 301 that would normally suppress β-pleated sheet formation, this combination of tau mutations increases the propensity for both secondary and tertiary structure needed for amyloid formation, thus allowing this double mutant to readily polymerize to form inclusions.…”

Section: Discussionmentioning

confidence: 99%

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Distinct differences in prion-like seeding and aggregation between Tau protein variants provide mechanistic insights into tauopathies

Strang¹,

Croft²,

Sorrentino³

et al. 2018

Journal of Biological Chemistry

139

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The accumulation of aberrantly aggregated microtubule-associated protein tau (MAPT) 1 defines a spectrum of tauopathies, including Alzheimer's disease. Mutations in the MAPT gene cause frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), characterized by neuronal pathological tau inclusions in the form of neurofibrillary tangles and Pick bodies, and in some cases glial tau pathology. Increasing evidence points to the importance of prion-like seeding as a mechanism for the pathological spread in tauopathy and other neurodegenerative diseases. Herein, using a cell culture model, we examined a multitude of genetic FTDP-17 tau variants for their ability to be seeded by exogenous tau fibrils. Our findings revealed stark differences between FTDP-17 tau variants in their ability to be seeded, with variants at proline 301 and serine 320 showing robust aggregation with seeding. Similarly, we elucidated the importance of certain tau protein regions and unique residues, including the role of proline 301 in inhibiting tau aggregation. We also revealed potential barriers in cross-seeding between 3-repeat and 4-repeat tau isoforms. Overall, these differences alluded to potential mechanistic differences between wild-type and FTDP-17 tau variants, as well as different tau isoforms, in influencing tau aggregation. Furthermore, by combining two FTDP-17 tau variants (either P301L or P301S with S320F), we generated aggressive models of tauopathy that does not require exogenous seeding. These models will allow for rapid screening of potential therapeutics to alleviate tau aggregation without the need for exogenous tau fibrils. Together, these studies provide novel insights in the molecular determinants that modulate tau aggregation.Tauopathies are a spectrum of neurodegenerative diseases characterized by the presence of pathological inclusions composed of aberrantly aggregated and hyperphosphorylated microtubule-associated protein tau (MAPT). Tauopathies are pathologically and phenotypically diverse, and include Alzheimer's disease (AD), progressive supranuclear palsy, corticobasal degeneration, chronic traumatic encephalopathy, Pick's disease, and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17)(1-4). Tau is abundant in neurons and expressed at lower levels in glia (1, 6, 7), and primarily stabilizes microtubules (MTs) among other diverse physiological functions (1,5,8,9). Six different isoforms of tau, ranging from 352 to 441 amino acids, are expressed in the adult human brain as a result of alternative splicing (10, 11). Differential splicing results in the inclusion or exclusion of the R2 MT-binding repeat, producing tau isoforms with either three (3R) or four (4R) repeats, respectively, and one or two N-terminal inserts (Figure 1).Over 50 mutations have been identified in the MAPT gene in families with 2,4,12 Tau Mutants and Seeding 2 disease, and patients typically experience disease onset at ~49 years of age with an average disease duration of 8.5 years (13). Certai...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Distinct differences in prion-like seeding and aggregation between Tau protein variants provide mechanistic insights into tauopathies

Strang¹,

Croft²,

Sorrentino³

et al. 2018

Journal of Biological Chemistry

139

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“…Mice inoculated with cell-passaged MSA contained significantly more α-synuclein prions than controls. ***P < 0.001, ****P < 0.0001. not feasible to generate, and only recently has cryo-electron microscopy (cryo-EM) enabled structural biologists to ascertain the structure of tau prions from an Alzheimer's disease patient (12). A handful of α-synuclein structures have been reported using synthetic fibrils, although many are based on highly ordered protein fragments (13)(14)(15)(16).…”

Section: Resultsmentioning

confidence: 99%

Familial Parkinson’s point mutation abolishes multiple system atrophy prion replication

Woerman

Kazmi

Patel

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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In the neurodegenerative disease multiple system atrophy (MSA), α-synuclein misfolds into a self-templating conformation to become a prion. To compare the biological activity of α-synuclein prions in MSA and Parkinson's disease (PD), we developed nine α-synuclein−YFP cell lines expressing point mutations responsible for inherited PD. MSA prions robustly infected wild-type, A30P, and A53T α-synuclein-YFP cells, but they were unable to replicate in cells expressing the E46K mutation. Coexpression of the A53T and E46K mutations was unable to rescue MSA prion infection in vitro, establishing that MSA α-synuclein prions are conformationally distinct from the misfolded α-synuclein in PD patients. This observation may have profound implications for developing treatments for neurodegenerative diseases.ultiple system atrophy (MSA) is a rapidly progressing neurodegenerative disease resulting in dysfunction of the autonomic nervous system and disrupted motor function. The pathological hallmark of MSA is the presence of α-synuclein aggregates that coalesce into glial cytoplasmic inclusions (GCIs) in oligodendrocytes (1). MSA is one of four synucleinopathies, the other three being Parkinson's disease (PD), Parkinson's disease with dementia (PDD), and dementia with Lewy bodies (DLB). In PD, PDD, and DLB patients, α-synuclein accumulates in neurons as Lewy bodies and Lewy neurites (2). Recent studies demonstrate that MSA is unequivocally caused by α-synuclein prions, which are misfolded proteins that undergo self-propagation and are capable of transmitting disease to transgenic (Tg) mice (3-6). Using TgM83 +/− mice, which express human α-synuclein with the familial A53T mutation, both intracranial (3, 5) and peripheral inoculation (6) of brain homogenate from a total of 17 MSA patients induced neurological disease in the animals. In addition, α-synuclein prions isolated from MSA patients propagated in cultured HEK cells that express mutant human α-synuclein*A53T fused to YFP (α-syn140*A53T−YFP) (4). While PD transmission studies have induced α-synuclein neuropathology (7-9), attempts to transmit disease to TgM83 +/− mice or to infect α-syn140*A53T−YFP cells have been unsuccessful (5), suggesting that distinct conformations of misfolded α-synuclein or α-synuclein prion strains may be responsible for these diseases.To study the strain-specific properties of α-synuclein prions in MSA patients and to reconcile the differences between PD and MSA prions, we conducted a series of studies to investigate the effect of inherited PD point mutations on MSA prion replication. In addition to the original WT (α-syn140-YFP) and α-syn140*A53T-YFP cells first reported in 2015 (4), we generated seven additional HEK cell lines expressing single mutations (A30P and E46K), double mutations (A30P,A53T and E46K,A53T), and truncated α-synuclein*A53T (residues 1-95, 1-97, and 29-97). After measuring MSA prion infection in the WT, A30P, and A53T cell lines, we were surprised to observe that the E46K mutation prevented the replication of MSA prions in vi...

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“…Recently, a study using cryo-electron microscopy facilitated a high resolution atomic characterization of the structures of the PHFs and straight filaments from the brain of an individual with Alzheimer's disease, establishing a basis for understanding the differences between molecular conformers of tau aggregates and showing how different isoforms are incorporated into the tau filaments [9].…”

Section: Isoforms and Biochemical Composition Of Filamentsmentioning

confidence: 99%

Untangling the tauopathies: Current concepts of tau pathology and neurodegeneration

Ling

2018

Parkinsonism & Related Disorders

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Cryo-EM structures of tau filaments from Alzheimer’s disease

Cited by 1,563 publications

References 58 publications

Distinct differences in prion-like seeding and aggregation between Tau protein variants provide mechanistic insights into tauopathies

Distinct differences in prion-like seeding and aggregation between Tau protein variants provide mechanistic insights into tauopathies

Familial Parkinson’s point mutation abolishes multiple system atrophy prion replication

Untangling the tauopathies: Current concepts of tau pathology and neurodegeneration

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