Cap‐independent translation of GPLD1 enhances markers of brain health in long‐lived mutant and drug‐treated mice. Issue 9 (5th August 2022)

• Record Type: Journal Article
• Authors: Li, Xinna; Shi, Xiaofang; McPherson, Madaline; Hager, Mary; Garcia, Gonzalo G.; Miller, Richard A.
• Is Part Of: Aging cell. Volume 21:Issue 9(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-08-05
• Subjects: aging -- cap‐independent translation -- glycosylphosphatidylinositol specific phospholipase D1 -- growth hormone; Cells -- Aging -- Periodicals; 571.8783605
• DOI: 10.1111/acel.13685
• Languages: English
• ISSNs: 1474-9718

Abstract

Abstract: Glycosylphosphatidylinositol‐specific phospholipase D1 (GPLD1) hydrolyzes inositol phosphate linkages in proteins anchored to the cell membrane. Mice overexpressing GPLD1 show enhanced neurogenesis and cognition. Snell dwarf (DW) and growth hormone receptor knockout (GKO) mice show delays in age‐dependent cognitive decline. We hypothesized that augmented GPLD1 might contribute to retained cognitive function in these mice. We report that DW and GKO show higher GPLD1 levels in the liver and plasma. These mice also have elevated levels of hippocampal brain‐derived neurotrophic factor (BDNF) and of doublecortin (DCX), suggesting a mechanism for maintenance of cognitive function at older ages. GPLD1 was not increased in the hippocampus of DW or GKO mice, suggesting that plasma GPLD1 increases elevated these brain proteins. Alteration of the liver and plasma GPLD1 was unaltered in mice with liver‐specific GHR deletion, suggesting that the GH effect was not intrinsic to the liver. GPLD1 was also induced by caloric restriction and by each of four drugs that extend lifespan. The proteome of DW and GKO mice is molded by selective translation of mRNAs, involving cap‐independent translation (CIT) of mRNAs marked by N 6 methyladenosine. Because GPLD1 protein increases were independent of the mRNA level, we tested the idea that GPLD1 might be regulated by CIT. 4EGI‐1, which enhances CIT, increased GPLD1 protein without changes in GPLD1 mRNA in cultured fibroblasts and mice. Furthermore, transgenic overexpression of YTHDF1, which promotes CIT by reading m6A signals, also led to increased GPLD1 protein, showing that elevation of GPLD1 reflects selective mRNA translation. Abstract : Two kinds of long‐lived mice, Snell dwarf and GHRKO, have higher levels of GPLD1 in liver and plasma, as well as higher levels of two GPLD1‐stimulated brain proteins, BDNF and DCX. Increased GPLD1 reflects selective cap‐independent mRNA translation rather than transcriptional changes. Last, GPLD1 can be increased, in cultured cells and in mice, by a transgene and by a drug that turns on cap‐independent translation.