# Examining the role of phosphatidylethanolamine and autophagic disruption in Lewy Body Dementias and Parkinson's disease

> **NIH NIH R56** · LOUISIANA STATE UNIV HSC SHREVEPORT · 2021 · $642,408

## Abstract

Deficits in the phospholipid phosphatidylethanolamine (PE) and its metabolites, such as ethanolamine
(ETA) and phosphoethanolamine, occur in the Parkinson’s disease (PD) and Alzheimer’s disease brain. We
propose that these metabolic deficits likely also occur in diseases characterized by synuclein pathology such as
dementia with Lewy bodies and multiple system atrophy. Whether these metabolic deficits are a cause or
consequence of disease is not known. However, we do know that low levels of PE can lead to mitochondrial
dysfunction, autophagy dysfunction, and the misprocessing of glycosylphosphatidylinositol-anchored proteins,
and that the homeostasis of α-syn can certainly be impacted by decrements in these processes. In fact, data
from yeast and worm models of synucleinopathies, have shown that the co-occurrence of low levels of PE (due
to knocking out the mitochondrial enzyme phosphatidylserine decarboxylase, PISD) and α-syn are synthetically
toxic. ETA rescues α-syn toxicity in PISD knockout cells, because ETA stimulates the synthesis of PE via the
CDP-ethanolamine pathway, which resides in the endoplasmic reticulum. The long-term goal of this proposed
research is to elucidate how α-syn modulates autophagy. To dissect the role of the PE-ETA axis in
synucleinopathies and the role of α-syn in inhibiting autophagy, our specific aims are to: (1) determine the role
of PE synthesis in autophagic-lysosomal function and clearance of α-syn in patient iPSC-neurons. We will
determine if stimulating PE synthesis with ETA will rescue autophagic phenotypes in patient neurons and
whether ETA decreases the accumulation of pathologic conformations of α-syn by increasing autophagic flux.
(2) Determine the mechanism by which α-syn (and A53T) decreases the level of PISD in patient iPSC-midbrain
and excitatory-cortical cells, and in SH-SY5Y cells. We propose that a deficit in PISD produces a deficit in PE
with a parallel inhibition of autophagy. We will determine whether α-syn (and A53T) blocks the import of PISD
into mitochondria by disrupting mitochondrial associated membranes (MAMs) that connect the ER with
mitochondria. Alternatively, α-syn (and A53T) may trigger the release of PISD from cells via endosomes or
promote the rapid degradation of the protein. These possibilities will be analyzed by electron microscopy,
isolation of mitochondria with attending lipid analysis, analysis of autophagy flux, and exosome isolation. (3)
Determine whether α-syn inhibits mitochondrion-vacuole and mitochondrion-ER contacts. We will knock out
genes that regulate mitochondrion-ER contacts and separately knockout genes that regulate mitochondrion-
vacuole contacts in cells with and without α-syn expression and then evaluate how disruptions in these
mitochondrion-organelle contacts affect the autophagic flux of Atg8-GFP. We have already shown that α-syn
inhibits the autophagic flux of Atg8-GFP, but these experiments dig deeper and will reveal whether the α-syn
inhibits autophagy...

## Key facts

- **NIH application ID:** 10419671
- **Project number:** 1R56NS114272-01A1
- **Recipient organization:** LOUISIANA STATE UNIV HSC SHREVEPORT
- **Principal Investigator:** Joseph R Mazzulli
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $642,408
- **Award type:** 1
- **Project period:** 2021-08-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10419671

## Citation

> US National Institutes of Health, RePORTER application 10419671, Examining the role of phosphatidylethanolamine and autophagic disruption in Lewy Body Dementias and Parkinson's disease (1R56NS114272-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10419671. Licensed CC0.

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