The Combination of Quantitative Proteomics and Systems Genetics Analysis Reveals that PTN Is Associated with Sleep-Loss-Induced Cognitive Impairment

Abstract

Sleep loss is associated with cognitive dysfunction. However, the detailed mechanisms remain unclear. In this study, we established a parachlorophenylalanine (PCPA)-induced insomniac mouse model with impaired cognitive function. Mass-spectrometry-based proteomics showed that the expression of 164 proteins was significantly altered in the hippocampus of the PCPA mice. To identify critical regulators among the potential markers, a transcriptome-wide association screening was performed in the BXD mice panel. Among the candidates, the expression of pleiotrophin (Ptn) was significantly associated with cognitive functions, indicating that Ptn-mediates sleep-loss-induced cognitive impairment. Gene co-expression analysis further revealed the potential mechanism by which Ptn mediates insomnia-induced cognitive impairment via the MAPK signaling pathway; that is, the decreased secretion of Ptn induced by insomnia leads to reduced binding to Ptprz1 on the postsynaptic membrane with the activation of the MAPK pathway via Fos and Nr4a1, further leading to the apoptosis of neurons. In addition, Ptn is genetically trans-regulated in the mouse hippocampus and implicated in neurodegenerative diseases in human genome-wide association studies. Our study provides a novel biomarker for insomnia-induced cognitive impairment and a new strategy for seeking neurological biomarkers by the integration of proteomics and systems genetics.

Isoglutaminyl Cyclase Overexpression Enhances KYSE30 Cancer Cell Proliferation and Migration via the MAPK Signaling Pathway

“…34 Mechanistically, pleiotrophin (Ptn) mediated insomnia-induced cognitive impairment via the MAPK signaling pathway. 35 And the MAPK pathway mediated piR-YBX1, a novel PIWIinteracting RNA, induced proliferation and metastasis of TNBC. 36 In the KYSE30 cell line overexpressing isoQC, p-ERK expression was inhibited while PER2 was increased, but the protein level of p-ERK was increased, while the protein level of PER2 was decreased significantly in the presence of KL044, indicating that upregulated isoQC might activate MAPK and Ras signaling pathways to promote the proliferation and migration abilities of cancer cells in vitro by upregulating the expression of PER2.…”

“…GINS2 interference attenuated cell viability, migration, and invasion in TC cell lines by inhibiting proteins in the MAPK signaling pathway, including JNK, ERK, and P38 . Mechanistically, pleiotrophin (Ptn) mediated insomnia-induced cognitive impairment via the MAPK signaling pathway . And the MAPK pathway mediated piR-YBX1, a novel PIWI-interacting RNA, induced proliferation and metastasis of TNBC .…”

Systems genetics identifies methionine as a high risk factor for Alzheimer's disease

“…In this study, we integrated phenotypic resources from the BXD panel, including more than 300 neural phenotypes from over 150 mouse strains. The recombinant inbred population of the BXD family, as one of the largest and well-characterized genetic reference populations, is the basis for studying various diseases, such as cancer, cognitive disorders, and heart diseases (Zhu et al, 2020 ; Bajpai et al, 2023 ; Zhou et al, 2023 ; Xu et al, 2024 ). The correlation of the BXD RI family has been extended to genetic analysis of behavioral phenotypes, including drug addiction, neurodegenerative processes, etc.…”