Evidence for the Existence of a Secondary Pathway for Fibril Growth during the Aggregation of Tau

Ramachandran, Gayathri; Udgaonkar, Jayant B.

doi:10.1016/j.jmb.2012.01.007

Cited by 59 publications

(71 citation statements)

References 84 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…24,25 As reported by other studies, [24][25][26][27][28][29][30][31][32] a reaction dominated by secondary nucleation undergoes an exponential increase in the early stages, as a result of the positive feedback. The positive feedback is a consequence of the fact that formed aggregates accelerate the rate of production of further aggregates.…”

Section: Secondary-nucleation Events Confirmed By the Kinetic Analysisupporting

confidence: 52%

“…2b and c). It was reported by others 24,25 that the primary nucleation pathway is following the quadratic in time,~t 2 , while the reaction dominated by secondary nucleation pathway undergoes an exponential increase in the early stages of the reaction. 24 The initial parts of our data with a 20 μM concentration, which was used for Aβ42 fibrillogenesis study, were fitted well by an exponential time function but poorly fitted by the t 2 function.…”

Section: Secondary-nucleation Events Confirmed By the Kinetic Analysimentioning

confidence: 95%

“…25 The lag time (t D ) was calculated using the formula t D = t 50 − 2s as described in Nielsen et al 30 Note that Eq. (1) is an empirical sigmoid fit function, and thus, the constants do not have an interpretation in terms of rates of molecular processes.…”

Section: Secondary-nucleation Events Confirmed By the Kinetic Analysimentioning

confidence: 99%

“…55 Moreover, Andersen et al have demonstrated that new fibrils of glucagon could be formed from preexisting ones by branching. 56 In addition, the kinetic signature of sigmoidal reaction showing the long lag phase followed by a rapid growth always indicates the generation of new aggregates during the aggregation of tau, 25 islet, 26,27 and insulin 30 fibrils. The nucleation reaction orders extracted from the kinetic curves allow us to distinguish the fibril fragmentation and surfacecatalyzed nucleation.…”

Section: Secondary Nucleation Is Fibril-type Specificmentioning

confidence: 99%

See 3 more Smart Citations

Novel Mechanistic Insight into the Molecular Basis of Amyloid Polymorphism and Secondary Nucleation during Amyloid Formation

Jeong

Ansaloni

Mezzenga

et al. 2013

Journal of Molecular Biology

129

142

View full text Add to dashboard Cite

The formation of amyloid β (Aβ) fibrils is crucial in initiating the cascade of pathological events that culminates in Alzheimer's disease. In this study, we investigated the mechanism of Aβ fibril formation from hydrodynamically well defined species under controlled aggregation conditions. We present a detailed mechanistic model that furnishes a novel insight into the process of Aβ42 fibril formation and the molecular basis for the different structural transitions in the amyloid pathway. Our data reveal the structure and polymorphism of Aβ fibrils to be critically influenced by the oligomeric state of the starting materials, the ratio of monomeric-to-aggregated forms of Aβ42 (oligomers and protofibrils), and the occurrence of secondary nucleation. We demonstrate that monomeric Aβ42 plays an important role in mediating structural transitions in the amyloid pathway, and for the first time, we provide evidences that Aβ42 fibrillization occurs via a combined mechanism of nucleated polymerization and secondary nucleation. These findings will have significant implications to our understanding of the molecular basis of amyloid formation in vivo, of the heterogeneity of Aβ pathology (e.g., diffuse versus amyloid plaques), and of the structural basis of Aβ toxicity.

show abstract

Section: Secondary-nucleation Events Confirmed By the Kinetic Analysisupporting

confidence: 52%

Section: Secondary-nucleation Events Confirmed By the Kinetic Analysimentioning

confidence: 95%

Section: Secondary-nucleation Events Confirmed By the Kinetic Analysimentioning

confidence: 99%

Section: Secondary Nucleation Is Fibril-type Specificmentioning

confidence: 99%

See 2 more Smart Citations

Novel Mechanistic Insight into the Molecular Basis of Amyloid Polymorphism and Secondary Nucleation during Amyloid Formation

Jeong

Ansaloni

Mezzenga

et al. 2013

Journal of Molecular Biology

129

142

View full text Add to dashboard Cite

show abstract

“…For three different protein systems (including both our own and others' data), we observe kinks in the lag-time versus concentration curves, at which the scaling exponent g changes. Other published datasets also show tantalizing hints of kinks, but with insufficient statistical certainty, or without a sufficiently wide concentration range to be sure (9,(27)(28)(29).…”

Section: Discussionmentioning

confidence: 99%

Competition between Primary Nucleation and Autocatalysis in Amyloid Fibril Self-Assembly

Eden

Morris

Gillam

et al. 2015

Biophysical Journal

View full text Add to dashboard Cite

Kinetic measurements of the self-assembly of proteins into amyloid fibrils are often used to make inferences about molecular mechanisms. In particular, the lag time--the quiescent period before aggregates are detected--is often found to scale with the protein concentration as a power law, whose exponent has been used to infer the presence or absence of autocatalytic growth processes such as fibril fragmentation. Here we show that experimental data for lag time versus protein concentration can show signs of kinks: clear changes in scaling exponent, indicating changes in the dominant molecular mechanism determining the lag time. Classical models for the kinetics of fibril assembly suggest that at least two mechanisms are at play during the lag time: primary nucleation and autocatalytic growth. Using computer simulations and theoretical calculations, we investigate whether the competition between these two processes can account for the kinks which we observe in our and others' experimental data. We derive theoretical conditions for the crossover between nucleation-dominated and growth-dominated regimes, and analyze their dependence on system volume and autocatalysis mechanism. Comparing these predictions to the data, we find that the experimentally observed kinks cannot be explained by a simple crossover between nucleation-dominated and autocatalytic growth regimes. Our results show that existing kinetic models fail to explain detailed features of lag time versus concentration curves, suggesting that new mechanistic understanding is needed. More broadly, our work demonstrates that care is needed in interpreting lag-time scaling exponents from protein assembly data.

show abstract

The Lys 280 → Gln mutation mimicking disease‐linked acetylation of Lys 280 in tau extends the structural core of fibrils and modulates their catalytic properties

Kumar

Udgaonkar

2021

Protein Science

Self Cite

View full text Add to dashboard Cite

Amyloid fibrillar aggregates isolated from the brains of patients with neurodegenerative diseases invariably have post‐translational modifications (PTMs). The roles that PTMs play in modulating the structures and polymorphism of amyloid aggregates, and hence their ability to catalyze the conversion of monomeric protein to their fibrillar structure is, however, poorly understood. This is particularly true in the case of tau aggregates, where specific folds of fibrillar tau have been implicated in specific tauopathies. Several PTMs, including acetylation at Lys 280, increase aggregation of tau in the brain, and increase neurodegeneration. In this study, tau‐K18 K280Q, in which the Lys 280 → Gln mutation is used to mimic acetylation at Lys 280, is shown, using HX‐MS measurements, to form fibrils with a structural core that is longer than that of tau‐K18 fibrils. Measurements of critical concentrations show that the binding affinity of monomeric tau‐K18 for its fibrillar counterpart is only marginally more than that of monomeric tau‐K18 K280Q for its fibrillar counterpart. Quantitative analysis of the kinetics of seeded aggregation, using a simple Michaelis–Menten‐like model, in which the monomer first binds and then undergoes conformational conversion to β‐strand, shows that the fibrils of tau‐K18 K280Q convert monomeric protein more slowly than do fibrils of tau‐K18. In contrast, monomeric tau‐K18 K280Q is converted faster to fibrils than is monomeric tau‐K18. Thus, the effect of Lys 280 acetylation on tau aggregate propagation in brain cells is expected to depend on the amount of acetylated tau present, and on whether the propagating seed is acetylated at Lys 280 or not.

show abstract

Evidence for the Existence of a Secondary Pathway for Fibril Growth during the Aggregation of Tau

Cited by 59 publications

References 84 publications

Novel Mechanistic Insight into the Molecular Basis of Amyloid Polymorphism and Secondary Nucleation during Amyloid Formation

Novel Mechanistic Insight into the Molecular Basis of Amyloid Polymorphism and Secondary Nucleation during Amyloid Formation

Competition between Primary Nucleation and Autocatalysis in Amyloid Fibril Self-Assembly

The Lys 280 → Gln mutation mimicking disease‐linked acetylation of Lys 280 in tau extends the structural core of fibrils and modulates their catalytic properties

Contact Info

Product

Resources

About