RT Journal Article
SR Electronic
T1 β-arrestin1 promotes tauopathy by transducing GPCR signaling, disrupting microtubules and autophagy
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202101183
DO 10.26508/lsa.202101183
VO 5
IS 3
A1 Woo, Jung-AA
A1 Yan, Yan
A1 Kee, Teresa R
A1 Cazzaro, Sara
A1 McGill Percy, Kyle C
A1 Wang, Xinming
A1 Liu, Tian
A1 Liggett, Stephen B
A1 Kang, David E
YR 2022
UL http://www.life-science-alliance.org/content/5/3/e202101183.abstract
AB G protein–coupled receptors (GPCRs) have been shown to play integral roles in Alzheimer’s disease pathogenesis. However, it is unclear how diverse GPCRs similarly affect Aβ and tau pathogenesis. GPCRs share a common mechanism of action via the β-arrestin scaffolding signaling complexes, which not only serve to desensitize GPCRs by internalization, but also mediate multiple downstream signaling events. As signaling via the GPCRs, β2-adrenergic receptor (β2AR), and metabotropic glutamate receptor 2 (mGluR2) promotes hyperphosphorylation of tau, we hypothesized that β-arrestin1 represents a point of convergence for such pathogenic activities. Here, we report that β-arrestins are not only essential for β2AR and mGluR2-mediated increase in pathogenic tau but also show that β-arrestin1 levels are increased in brains of Frontotemporal lobar degeneration (FTLD-tau) patients. Increased β-arrestin1 in turn drives the accumulation of pathogenic tau, whereas reduced ARRB1 alleviates tauopathy and rescues impaired synaptic plasticity and cognitive impairments in PS19 mice. Biochemical and cellular studies show that β-arrestin1 drives tauopathy by destabilizing microtubules and impeding p62/SQSTM1 autophagy flux by interfering with p62 body formation, which promotes pathogenic tau accumulation.