Major Differences between the Self-Assembly and Seeding
Behavior of Heparin-Induced and in Vitro Phosphorylated Tau and Their
Modulation by Potential Inhibitors
Version 3 2019-08-21, 15:03
Version 2 2019-07-16, 23:43
Version 1 2019-05-15, 14:06
Posted on 2019-08-21 - 15:03
Self-assembly of
the microtubule-associated protein tau into neurotoxic
oligomers, fibrils, and paired helical filaments, and cell-to-cell
spreading of these pathological tau species are critical processes
underlying the pathogenesis of Alzheimer’s disease and other
tauopathies. Modulating the self-assembly process and inhibiting formation
and spreading of such toxic species are promising strategies for therapy
development. A challenge in investigating tau self-assembly in vitro
is that, unlike most amyloidogenic proteins, tau does not aggregate
in the absence of posttranslational modifications (PTM), aggregation
inducers, or preformed seeds. The most common induction method is
addition of polyanions, such as heparin; yet, this artificial system
may not represent adequately tau self-assembly in vivo, which is driven
by aberrant phosphorylation and other PTMs, potentially leading to
in vitro data that do not reflect the behavior of tau and its interaction
with modulators in vivo. To tackle these challenges, methods for in
vitro phosphorylation of tau to produce aggregation-competent forms
recently have been introduced (Despres
et al. (2017) Proc. Natl. Acad. Sci. U.S.A., 114, 9080−9085). However, the oligomerization, seeding, and interaction
with assembly modulators of the different forms of tau have not been
studied to date. To address these knowledge gaps, we compared here
side-by-side the self-assembly and seeding activity of heparin-induced
tau with two forms of in vitro phosphorylated tau and tested how the
molecular tweezer CLR01, a negatively charged compound, affected these
processes. Tau was phosphorylated by incubation either with activated
extracellular signal-regulated kinase 2 or with a whole rat brain
extract. Seeding activity was measured using a fluorescence-resonance
energy transfer-based biosensor-cell method. We also used solution-state
NMR to investigate the binding sites of CLR01 on tau and how they
were impacted by phosphorylation. Our systematic structure–activity
relationship study demonstrates that heparin-induced tau behaves differently
from in vitro phosphorylated tau. The aggregation rates of the different
forms are distinct as is the intracellular localization of the induced
aggregates, which resemble brain-derived tau strains suggesting that
heparin-induced tau and in vitro phosphorylated tau have different
conformations, properties, and activities. CLR01 inhibits aggregation
and seeding of both heparin-induced and in vitro phosphorylated tau
dose-dependently, although heparin induction interferes with the interaction
between CLR01 and tau.
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Despres, Clément; Di, Jing; Cantrelle, François-Xavier; Li, Zizheng; Huvent, Isabelle; Chambraud, Béatrice; et al. (2019). Major Differences between the Self-Assembly and Seeding
Behavior of Heparin-Induced and in Vitro Phosphorylated Tau and Their
Modulation by Potential Inhibitors. ACS Publications. Collection. https://doi.org/10.1021/acschembio.9b00325
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AUTHORS (18)
CD
Clément Despres
JD
Jing Di
FC
François-Xavier Cantrelle
ZL
Zizheng Li
IH
Isabelle Huvent
BC
Béatrice Chambraud
JZ
Jing Zhao
JC
Jianle Chen
SC
Shiguo Chen
GL
Guy Lippens
FZ
Fuming Zhang
RL
Robert Linhardt
CW
Chunyu Wang
FK
Frank-Gerrit Klärner
TS
Thomas Schrader
IL
Isabelle Landrieu
GB
Gal Bitan
CS
Caroline Smet-Nocca
KEYWORDS
fluorescence-resonance energy transfer-based biosensor-cell methodphosphorylated tauphosphorylated tau dose-dependentlyPTMextracellular signal-regulated kinase 2brain-derived tau strainsmicrotubule-associated protein tautau self-assemblyCLR 01NMRVitro Phosphorylated TauU.S.Aheparin-induced tauPotential Inhibitors Self-assembly