Increased palmitoylation improves estrogen receptor alpha–dependent hippocampal synaptic deficits in a mouse model of synucleinopathy

• DOI: 10.1126/sciadv.adj1454
• Publication Date: 2023-11-17T19:01:01Z
• Authors: Tim E. Moors; Shaomin Li; Thomas D. McCaffery; Gary P. H. Ho; Pascal A. Bechade; Luu N. Pham; Maria Ericsson; Silke Nuber
• Keywords: Palmitoylation; Estrogen receptor alpha; Homeostasis

Parkinson’s disease (PD) is characterized by conversion of soluble α-synuclein (αS) into intraneuronal aggregates and degeneration neurons neuronal processes. Indications that women with early-stage PD display milder neurodegenerative features suggest female sex partially protects against αS pathology. We previously reported estradiol improved homeostasis PD-like phenotypes in E46K-amplified (3K) mice. Here, we aimed to further dissect mechanisms drive this dimorphism early disease. observed synaptic abnormalities were delayed females estradiol, mediated local estrogen receptor alpha (ERα). Aberrant ERα distribution 3K compared wild-type mice was paired its decreased palmitoylation. Treatment ML348, a de-palmitoylation inhibitor, increased availability homeostasis, ameliorating plasticity cognitive motor phenotypes. Our finding differences early-disease αS–induced impairment 3KL are part palmitoylated may have functional pathogenic implications for clinical PD.