AMPKα2 signals amino acid insufficiency to inhibit protein synthesis.

AMPKα2 may be a key player in sensing amino acid levels and regulating protein synthesis, with implications for Alzheimer's disease, but further research is needed to confirm these findings in humans.

Summary and findings

This study investigates the role of AMPKα2 in signaling amino acid insufficiency and its effects on protein synthesis. The findings are based on blood samples from a cohort of 1,000,000 Chinese individuals and mouse models. Loss of AMPKα2 was associated with cognitive dysfunction and altered protein synthesis.

Abstract

The functional difference between the two catalytic subunits, α1 and α2, of AMP-activated protein kinase (AMPK) complexes remains elusive. Herein, we report that AMPKα2 specifically transduces amino acid insufficiency signals to protein synthesis. Low amino acid levels, high protein levels, and reduced phosphorylation of AMPKα threonine 172 (p-T172) are observed in blood samples in patients with Alzheimer's disease (AD) from a cohort of 1,000,000 Chinese individuals. Loss of α2, but not α1, recaptures these observations and induces AD-like cognitive dysfunction in mice. Mechanistically, low amino acid-activated general control nonderepressible 2 (GCN2) specifically phosphorylates α2 at T172 independent of AMP and fructose 1,6-bisphosphate to inhibit protein synthesis. α2-p-T172 loss renders protein over-synthesis and AD-pathologic protein aggregation in cells and in mouse brain. AMPK activators metformin and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), as well as branched-chain amino acid (BCAA) or protein restriction, α2-p-T172-dependently prevent AD-like symptoms in mice. We identify AMPKα2 as a specific amino acid abundance detector for protein synthesis.

Limitations

Not reported in abstract.

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