Moors_2023_Sci.Adv_9_eadj1454

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