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

Author:

Moors Tim E.1ORCID,Li Shaomin1ORCID,McCaffery Thomas D.1ORCID,Ho Gary P. H.1ORCID,Bechade Pascal A.1,Pham Luu N.2ORCID,Ericsson Maria3ORCID,Nuber Silke1

Affiliation:

1. Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

2. Laboratory for Drug Discovery in Neurodegeneration, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

3. Electron Microscopy Laboratory, Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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