posted on 2023-08-23, 20:12authored byYutong Zhou, Hui Li, Xiaoya Liu, Xiaodong Chi, Zhaoxi Gu, Binsen Cui, Jonas Bergquist, Binsheng Wang, Geng Tian, Chunhua Yang, Fuyi Xu, Jia Mi
Sleep loss is associated with cognitive dysfunction.
However, the
detailed mechanisms remain unclear. In this study, we established
a para-chlorophenylalanine (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.