| dc.contributor.advisor | Zweckstetter, Markus Prof. Dr. | |
| dc.contributor.author | Chakraborty, Pijush | |
| dc.date.accessioned | 2022-11-28T15:38:25Z | |
| dc.date.available | 2022-12-05T00:50:09Z | |
| dc.date.issued | 2022-11-28 | |
| dc.identifier.uri | http://resolver.sub.uni-goettingen.de/purl?ediss-11858/14370 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-9588 | |
| dc.format.extent | 213 Seiten | de |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
| dc.subject.ddc | 570 | de |
| dc.title | Investigation on the molecular factors driving the formation of distinct tau 'strains' | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Zweckstetter, Markus Prof. Dr. | |
| dc.date.examination | 2021-12-07 | de |
| dc.description.abstracteng | Pathological aggregation of the microtubule-binding protein tau into amyloid fibrils is a
hallmark of different neurodegenerative diseases collectively termed tauopathies. To date,
tau amyloid structures associated with different tauopathies (Alzheimer’s disease, Chronic
traumatic encephalopathy, Corticobasal degeneration, Progressive supranuclear palsy,
Globular glial tauopathies, and Pick’s disease) have been determined. Strikingly, structures
are homogeneous within one disease, but differ significantly between different diseases,
suggesting a critical interplay between the amyloid structure, the nature of the disease and
its propagation. The distinct aggregate structures, termed amyloid "strains", can induce tau
aggregation in cellulo and recapitulate pathological phenotypes when injected into animals.
So far, the emergence of such tau amyloid strains remains elusive, and the factors that drive
tau aggregation towards a well-defined strain are unknown.
Recombinant tau monomers can efficiently form fibrils in vitro but only in the presence
of negatively charged co-factors such as heparin. However, the biological relevance of cofactor-
induced fibrillization as an in vitro model of tau aggregation has been questioned.
Indeed, cryo-electron microscopy (cryoEM) of heparin-induced fibrils of the longest isoform
of tau demonstrated that the heparin-induced fibrils differ structurally from the tau filaments
extracted from the human patient brain. Another major drawback of the heparin-based in
vitro fibrilization assay is the high negative charge of the heparin: heparin-induced tau
fibrillization has been extensively used to search for small molecules as tau aggregation
inhibitors, potentially generating false positives due to electrostatic interactions between the
small molecules and heparin.
Here we show that full-length tau protein can be aggregated in the absence of cofactors
into seeding-competent amyloid fibrils that sequester RNA. Using a combination of
solid-state NMR spectroscopy and biochemical experiments, we demonstrate that the cofactor-
free amyloid fibrils of 4R tau and 3R tau have a rigid core that is similar in size and
location to the rigid core of tau fibrils purified from the brain of patients with corticobasal
degeneration and Pick’s disease, respectively. In addition, we demonstrate that the Nterminal
30 residues of tau are immobilized during fibril formation, in agreement with the
VII
presence of an N-terminal epitope that is specifically detected by antibodies in pathological
tau. Experiments in vitro and in biosensor cells further established that co-factor-free tau
fibrils efficiently seed tau aggregation, while binding studies with different RNAs show that
the co-factor-free tau fibrils strongly sequester RNA.
Tau can be modified by numerous post-translational modifications (PTMs) in vivo.
Based on the inception of tau pathology in a particular region of the brain, different brain
regions can exert different PTMs that might influence tau filaments' structure in different
tauopathies. Among all the PTMs, acetylation of lysine residues in tau is one of the critical
PTMs observed in different tauopathies, and reducing the acetylated tau is neuroprotective
in brain injuries. Here we show that acetylation can discriminate disease and isoform-specific
tau by accelerating the aggregation of 3R tau and inhibiting the aggregation of 4R tau. Our
data further reveal the critical role played by five lysine residues present in the R2 domain of
tau, especially K298, in inhibiting 4R tau aggregation upon acetylation. Thus, our findings
identify acetylation as a critical molecular factor to specifically deposit the 3R isoform of tau.
Taken together, our work provides a critical advancement in revealing the molecular factors
that guide aggregation towards disease-specific tau strains shedding light on the enigmatic
emergence of 3R tauopathies. | de |
| dc.contributor.coReferee | Kügler, Sebastian Dr. | |
| dc.contributor.thirdReferee | Faesen, Alex Dr. | |
| dc.contributor.thirdReferee | Urlaub, Henning Prof. Dr. | |
| dc.contributor.thirdReferee | Söding, Johannes Dr. | |
| dc.contributor.thirdReferee | Fernández-Busnadiego, Rubén Prof. Dr. | |
| dc.subject.eng | tauopathies | de |
| dc.subject.eng | neurodegeneration | de |
| dc.subject.eng | post-translational modifications | de |
| dc.subject.eng | amyloid fibrils | de |
| dc.subject.eng | co-factor-free aggregation of tau | de |
| dc.subject.eng | Alzheimer's disease | de |
| dc.subject.eng | acetylation | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-ediss-14370-1 | |
| dc.affiliation.institute | Biologische Fakultät für Biologie und Psychologie | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.description.embargoed | 2022-12-05 | de |
| dc.identifier.ppn | 1826746137 | |
| dc.identifier.orcid | 0000-0003-1749-5225 | de |
| dc.notes.confirmationsent | Confirmation sent 2022-11-28T15:45:02 | de |