O‐GlcNAcylation of protein kinase A catalytic subunits enhances its activity: a mechanism linked to learning and memory deficits in Alzheimer's disease. Issue 3 (3rd February 2016)

• Record Type: Journal Article
• Authors: Xie, Shutao; Jin, Nana; Gu, Jianlan; Shi, Jianhua; Sun, Jianming; Chu, Dandan; Zhang, Liang; Dai, Chun‐ling; Gu, Jin‐hua; Gong, Cheng‐Xin; Iqbal, Khalid; Liu, Fei
• Is Part Of: Aging cell. Volume 15:Issue 3(2016)
• Page Start: 455
• Page End: 464
• Publication Date: 2016-02-03
• Subjects: Alzheimer's disease -- learning and memory -- O‐GlcNAcylation -- protein kinase A; Cells -- Aging -- Periodicals; 571.8783605
• DOI: 10.1111/acel.12449
• Languages: English
• ISSNs: 1474-9718

Abstract

Summary: Alzheimer's disease (AD) is characterized clinically by memory loss and cognitive decline. Protein kinase A (PKA)‐CREB signaling plays a critical role in learning and memory. It is known that glucose uptake and O‐GlcNAcylation are reduced in AD brain. In this study, we found that PKA catalytic subunits (PKAcs) were posttranslationally modified by O‐linked N ‐acetylglucosamine (O‐GlcNAc). O‐GlcNAcylation regulated the subcellular location of PKAcα and PKAcβ and enhanced their kinase activity. Upregulation of O‐GlcNAcylation in metabolically active rat brain slices by O ‐(2‐acetamido‐2‐deoxy‐d ‐glucopyranosylidenamino) N ‐phenylcarbamate (PUGNAc), an inhibitor of N ‐acetylglucosaminidase, increased the phosphorylation of tau at the PKA site, Ser214, but not at the non‐PKA site, Thr205. In contrast, in rat and mouse brains, downregulation of O‐GlcNAcylation caused decreases in the phosphorylation of CREB at Ser133 and of tau at Ser214, but not at Thr205. Reduction in O‐GlcNAcylation through intracerebroventricular injection of 6‐diazo‐5‐oxo‐l ‐norleucine (DON), the inhibitor of glutamine fructose‐6‐phosphate amidotransferase, suppressed PKA‐CREB signaling and impaired learning and memory in mice. These results indicate that in addition to cAMP and phosphorylation, O‐GlcNAcylation is a novel mechanism that regulates PKA‐CREB signaling. Downregulation of O‐GlcNAcylation suppresses PKA‐CREB signaling and consequently causes learning and memory deficits in AD.