Tim E. Moors, United States of America

Brigham and Women's Hospital & Harvard Medical School Neurology

Tim Moors is a Postdoctoral Research Fellow at the Brigham and Women's Hospital and Harvard Medical School in Boston, USA. In 2020, he finished his PhD project at the Amsterdam University Medical Center, department of Anatomy and Neuroscience, during which he studied determinants for alpha-synuclein pathology in Parkinson’s Disease postmortem brain. In particular, he focused his work on the post-translational regulation of alpha-synuclein and its interplay with protein degradation pathways. In his current research, he strives to dissect cellular events involved in a protective effect of female sex and estrogen in alpha-synuclein-induced synaptic pathologies in mouse model of synucleinopathy (“3K alpha-synuclein mice) and associated cognitive impairment. This goal is pursued by combining behavioral, electrophysiological, and biochemical methods with state-of-the-art microscopy techniques such as stimulated emission depletion (STED) super-resolution microscopy and electron microscopy. He will present his initial findings in this project during the On Demand Session "Sex and Gender in Neurodegenerative Disease" on Sunday, March 14th, 8:00-10:00 and during the Live Discussion later the same day (on 15:30-16:00). For a list of his publications: https://pubmed.ncbi.nlm.nih.gov/?term=tim+moors%5BAuthor%5D&sort=relevance

Presenter of 2 Presentations

Conference Calendar

FEMALE SEX BENEFITS SYNAPTIC FUNCTION IN FAMILIAL PARKINSON’S DISEASE E46K-AMPLIFIED 3K ALPHA-SYNUCLEIN MICE: A POTENTIAL ROLE FOR ESTROGEN RECEPTORS

Session Name

SEX AND GENDER IN NEURODEGENERATIVE DISEASES

Session Type

SYMPOSIUM

Date

14.03.2021, Sunday

Session Time

08:00 - 10:00

Room

On Demand Symposia B

Lecture Time

08:45 - 09:00

Presenter

Tim E. Moors, United States of America

Session Icon

Abstract

Abstract

Aims

The familial Parkinson's Disease (PD) E46K mutation - being promoted by its amplification (‘3K’) - impairs normal alpha-synuclein (αS) homeostasis by increased binding to vesicle membranes, resulting in neuronal loss and a robust PD-like motor decline in 3K mice. Resembling clinical PD, female sex delays phenotypes in 3K mice, while estrogen treatment increases dopamine neurite fiber densities and vesicle turnover, suggesting neuroprotective action at the synaptic site. In this study, we further investigate estrogen effects of female sex on αS-induced synaptic pathophysiology in low expressing (‘3KL’) αS mutant mice.

Methods

We longitudinally analyzed motor and cognitive performance of 3KL and wild-type (WT) αS-expressing mice using open field, gait-scan and Morris-Water Maze. Synaptic plasticity was analyzed by electrophysiological measurements of acute striatal and hippocampal slices. αS solubility was evaluated by sequential extractions and cytopathology dissected using STED, confocal, and immuno-EM.

Results

At 6 and 12 months, changes in gait, explorative behavior and spatial memory were more pronounced in male vs. female 3KL compared to WT mice. In the cortex and hippocampus, STED and EM analyses showed that the multifold membrane-association of 3K compared to WT αS resulted in serine 129 phosphorylated αS+ profiles in somata, neurites and at synaptic vesicle clusters, which was paralleled by subcellular redistribution of estrogen receptor alpha (ERα). Further, electrophysiological recordings revealed estrogen-modulated long-term potentiation deficits in 3KL mice.

Conclusions

The present study highlights ERα as a new player in αS-induced synaptic pathologies. Since synaptic ERα availability preserves neuronal function, our study supports its targeting may benefit PD.

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LIVE DISCUSSION