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 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.

 

Comments:

This research sounds intriguing! It seems like the study delves into the potential protective role of female sex and estradiol in Parkinson's disease (PD) by focusing on α-synuclein (αS) pathology and synaptic abnormalities in mice models.

The observation that women with early-stage PD exhibit milder neurodegenerative features suggests a potential protective effect from αS pathology, and your study aims to dissect the mechanisms behind this sex dimorphism in the early stages of the disease.

The involvement of estrogen receptor alpha (ERα) and its localization in synaptic abnormalities is interesting. The observed aberrant distribution of ERα in 3K mice, along with decreased palmitoylation, suggests a potential link between ERα, synaptic function, and αS pathology in PD.

The use of ML348, a de-palmitoylation inhibitor, to modulate ERα availability and soluble αS homeostasis, resulting in the improvement of synaptic plasticity and cognitive and motor phenotypes, is a significant finding. It implies a potential therapeutic avenue by targeting ERα and palmitoylation mechanisms to mitigate synaptic impairment and associated PD symptoms.

Understanding the role of sex dimorphism and the mechanisms involved in synaptic impairment due to αS pathology in PD can indeed have significant implications for clinical interventions and therapeutic approaches.

Are there specific aspects or details of the research you'd like to discuss or explore further?

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