PUBLICATION
READ MORE-
[231201 저널발표] Amelioration of Tau and ApoE4-linked glial lipid accumulation and neurodegeneration with an LXR agonist
2023.11.30 -
[231201 저널발표] Increased palmitoylation improves estrogen receptor alpha-dependent hippocampal synaptic deficits in a mouse model of synucleinopathy
Sci Adv. 2023 Nov 15;9(46):eadj1454. doi: 10.1126/sciadv.adj1454. Epub 2023 Nov 17.Increased palmitoylation improves estrogen receptor alpha-dependent hippocampal synaptic deficits in a mouse model of synucleinopathyTim E Moors 1, Shaomin Li 1, Thomas D McCaffery 1, Gary P H Ho 1, Pascal A Bechade 1, Luu N Pham 2, Maria Ericsson 3, Silke Nuber 1Affiliations expandPMID: 37976363 DOI: 10.1126/sciadv.adj1454Free articleAbstractParkinson's disease (PD) is characterized by conversion of soluble α-synuclein (αS) into intraneuronal aggregates and degeneration of neurons and neuronal processes. Indications that women with early-stage PD display milder neurodegenerative features suggest that female sex partially protects against αS pathology. We previously reported that female sex and estradiol improved αS homeostasis and PD-like phenotypes in E46K-amplified (3K) αS mice. Here, we aimed to further dissect mechanisms that drive this sex dimorphism early in disease. We observed that synaptic abnormalities were delayed in females and improved by estradiol, mediated by local estrogen receptor alpha (ERα). Aberrant ERα distribution in 3K compared to wild-type mice was paired with its decreased palmitoylation. Treatment with ML348, a de-palmitoylation inhibitor, increased ERα availability and soluble αS homeostasis, ameliorating synaptic plasticity and cognitive and motor phenotypes. Our finding that sex differences in early-disease αS-induced synaptic impairment in 3KL mice are in part mediated by palmitoylated ERα may have functional and pathogenic implications for clinical PD. 2023.11.29