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

Parkinson's disease (PD) is characterized by conversion of soluble alpha-synuclein (alpha S) 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 alpha S pathology. We previously reported that female sex and estradiol improved alpha S homeostasis and PD-like phenotypes in E46K-amplified (3K) alpha S 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 (ER alpha). Aberrant ER alpha distribution in 3K compared to wild-type mice was paired with its decreased palmitoylation. Treatment with ML348, a de-palmitoylation inhibitor, increased ER alpha availability and soluble alpha S homeostasis, ameliorating synaptic plasticity and cognitive and motor phenotypes. Our finding that sex differences in early-disease alpha S-induced synaptic impairment in 3KL mice are in part mediated by palmitoylated ER alpha may have functional and pathogenic implications for clinical PD.