Accelerated Filament Formation From Tau Protein With Specific FTDP-17 Missense Mutations

Nacharaju, Parimala; Lewis, Jada; Easson, Colin; Yen, Shu‐Hui; Hackett, J.M.; Hutton, Michael

doi:10.1097/00005072-199905000-00157

Cited by 80 publications

(105 citation statements)

References 5 publications

Supporting

Mentioning

100

Contrasting

Order By: Relevance

“…Additionally, some tau missense mutants can negatively affect MT assembly and binding affinity (1,(14)(15)(16), alter tau's interaction with other protein complexes (17) and influence post-translational modifications (18). Furthermore, in vitro tau filament assembly studies have shown that some mutations cause tau to more readily self-aggregate compared to wild-type (WT) tau (15,19,20).While many functional consequences of tau mutations have been documented, differences between tau mutants regarding aggregation with seeding, however, are not well characterized. Tau aggregation is thought to occur in a nucleationdependent manner, with an initial lag phase followed by a more rapid elongation phase, as protein subunits are added to the growing tau fibril (21).…”

mentioning

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

107

139

View full text Add to dashboard Cite

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...

show abstract

mentioning

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

107

139

View full text Add to dashboard Cite

show abstract

“…This reduces the ability of tau to interact with microtubules, suggesting that this interaction is crucial for preventing the self-assembly of tau (Hasegawa et al 1998). Some mutations also promote the assembly of tau into filaments (Goedert et al 1999;Nacharaju et al 1999). Mutations having their primary effect at the RNA level are intronic or exonic and increase the alternative mRNA splicing of exon 10.…”

Section: Mutations In Maptmentioning

confidence: 99%

Frontotemporal Dementia: Implications for Understanding Alzheimer Disease

Goedert¹,

Ghetti²,

Spillantini³

2011

Cold Spring Harbor Perspectives in Medicine

138

View full text Add to dashboard Cite

“…In vitro studies demonstrated that mutations, including K257T, G272V, K280, N296, P301L, P301S, V337M, and R406W, promote heparin-or arachidonic acid-induced tau filament formation relative to wild type tau [114][115][116][117][118]. The missense tau gene mutations may also affect tau function by altering its phosphorylation state, and several mutations decrease the binding affinity of tau for protein phosphatase 2A, a major phosphatase implicated in the regulation of the MT-binding activity of tau [119].…”

Section: Structure Function and Molecular Genetics Of Taumentioning

confidence: 99%

The cytoskeleton in neurodegenerative diseases

Cairns

Lee

Trojanowski

2004

The Journal of Pathology

167

114

View full text Add to dashboard Cite

In vitro and transgenic animal models are being used to demonstrate that different mutations impair protein function, promote tau fibrilization, or perturb tau gene splicing, leading to aberrant and distinct tau aggregates. For recognition of these disorders at neuropathological examination, immunohistochemistry is needed, and this may be combined with biochemistry and molecular genetics to properly determine the nosology of a particular case. As reviewed here, the identification of molecular genetic defects and biochemical alterations in cytoskeletal proteins of human neurodegenerative diseases has facilitated experimental studies and will promote the development of assays of molecules which inhibit abnormal neuronal IF and tau protein inclusions.

show abstract

Accelerated Filament Formation From Tau Protein With Specific FTDP-17 Missense Mutations

Cited by 80 publications

References 5 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

Frontotemporal Dementia: Implications for Understanding Alzheimer Disease

The cytoskeleton in neurodegenerative diseases

Contact Info

Product

Resources

About