Cap‐independent translation of GPLD1 enhances markers of brain health in long‐lived mutant and drug‐treated mice

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 N6 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.

Aging Rate Indicators: Speedometers for Aging Research in Mice

“…GPLD1 is also detectable in the brain, but its levels seem to be controlled independently of liver and plasma GPLD1. Hippocampal GPLD1 is not altered in Snell or GHRKO mice 36 or in 18-month-old Ames mice 18 , or in PKO mice 19 . Nor does hippocampal GPLD1 protein increase in YTHDF1 transgenic mice 36 .…”

“…Physical exercise increases plasma levels of GPLD1 in mice and in humans, and increases in GPLD1 might contribute to beneficial effects of exercise on cognitive function. We have reported increased levels of GPLDL1 protein in liver and plasma of young adult Snell and GHRKO mice 36 , as well as in 18-month-old Ames dwarf mice 18 . Consistent with the results in mice overexpressing GPLD1, we found elevations of brain-derived neurotrophic factor (BDNF), which helps maintain CNS function, and of doublecortin (DCX), an indicator of increased neurogenesis, in these slow-aging mutant mice 36 .…”

“…We have reported increased levels of GPLDL1 protein in liver and plasma of young adult Snell and GHRKO mice 36 , as well as in 18-month-old Ames dwarf mice 18 . Consistent with the results in mice overexpressing GPLD1, we found elevations of brain-derived neurotrophic factor (BDNF), which helps maintain CNS function, and of doublecortin (DCX), an indicator of increased neurogenesis, in these slow-aging mutant mice 36 . The changes in liver production of GPLD1 seem not to reflect a direct effect of GH on liver cells, because they are not seen in mice in which the GH receptor has been disrupted in liver only, and additional studies will be needed to learn which GH-sensitive tissue(s) modulate liver GPLD1 synthesis.…”

“…The increase in liver GPLD1 protein in Snell and GHRKO mice is not accompanied by a corresponding increase in GPLD1 mRNA 36 , suggesting the idea that GPLD1 protein levels might be regulated by selective mRNA translation. In support of this idea, we found that liver GPLD1 was elevated in transgenic mice overexpressing YTHDF1, which promotes synthesis of multiple CIT proteins by enabling m6A-dependent translation from sites downstream of the 5-prime cap.…”

The role of GPLD1 in chronic diseases

“…A recent study has shown that increasing systemic concentration of GPLD1 in aged mice can alleviate aging‐related regenerative and cognitive impairments by altering signaling cascade cleavage of downstream GPI‐anchored substrates (Horowitz et al, 2020). Similarly, cap‐independent translation of GPLD1 in the liver can indirectly result in the changes of proteins in brain, which may lead to the beneficial effects on improving cognitive capacity and delaying aging‐related cognitive decline (Li et al, 2022). As a gene of dopamine D2 receptor (DRD2) coexpression network, GPLD1 is considered to be associated with multiple schizophrenia risk (Wang et al, 2018).…”