Aggregation of Microtubule Binding Repeats of Tau
Protein is Promoted by Cu2+
Posted on 2019-03-15 - 08:14
Understanding the factors that give
rise to tau aggregation and
reactive oxygen species (ROS) is the key aspect in Alzheimer’s
disease pathogenesis. Microtubule (MT) binding repeats of tau protein
were suggested to play a critical role in tau aggregation. Here, we
show that the interaction of Cu2+ with full-length MT binding
repeats R1–R4 leads to the aggregation, and a Cys-based redox
chemistry is critically involved in tau aggregation leading to disulfide-bridge
dimerization of R2 and R3 and further aggregation into a fibrillar
structure. Notably, ascorbate and glutathione, the most abundant antioxidants
in neurons, cannot prevent the effect of Cu2+ on R2 and
R3 aggregation. Detailed ESI-MS and NMR experiments demonstrate the
interaction of Cu2+ with MT binding repeats. We show that
redox activity of copper increases when bound to the MT repeats leading
to ROS formation, which significantly contribute to cellular damage
and neuron death. Results presented here provide new insights into
the molecular mechanism of tau aggregation and ROS formation and suggest
a new target domain for tau aggregation inhibitors.
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Ahmadi, Soha; Zhu, Shaolong; Sharma, Renu; Wu, Bing; Soong, Ronald; Majumdar, R. Dutta; et al. (2019). Aggregation of Microtubule Binding Repeats of Tau
Protein is Promoted by Cu2+. ACS Publications. Collection. https://doi.org/10.1021/acsomega.8b03595
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AUTHORS (9)
SA
Soha Ahmadi
SZ
Shaolong Zhu
RS
Renu Sharma
BW
Bing Wu
RS
Ronald Soong
RM
R. Dutta Majumdar
DW
Derek J. Wilson
AS
Andre J. Simpson
HK
Heinz-Bernhard Kraatz