# Investigating the role of lipid metabolism in protein aggregation and neurodegenerative disease progression

> **NIH NIH R01** · SEATTLE INST FOR BIOMEDICAL/CLINICAL RES · 2021 · $39,835

## Abstract

PROJECT SUMMARY
 Pathogenic protein aggregates are a hallmark neuropathologic finding in many
neurodegenerative diseases. Most research has thus far focused on how these pathogenic
aggregates are formed. However, little is known about the mechanism by which aggregates
spread from cell to cell, a hallmark of neurodegenerative disease progression. Parkinson's
disease (PD) is the second most common neurodegenerative disease. Mutations in the gene
glucosidase beta acid 1 (GBA), which encodes a lysosomal enzyme producing ceramide, are the
strongest genetic risk factor for PD. Recently, GBA mutations were also found to associate with
accelerated cognitive and motor symptom progression, suggesting that GBA mutations influence
the spread of protein aggregates within the brain. Recent work in PD and other neurodegenerative
diseases suggest that dysregulation of lipid metabolism, and in particular ceramide, also has an
important role in pathogenesis. Our recent work revealed a novel function for GBA in regulating
extracellular vesicle (EVs) formation and cargo. I hypothesize that GBA deficiency mediates faster
propagation of protein aggregates from cell to cell through dysregulation of EVs. To investigate
the mechanisms by which GBA mutations influence the propagation of protein aggregates
between tissues and between cells, I will use Drosophila, mouse and human neuronal cell culture
models of GBA deficiency. I hypothesize that decreased ceramide levels due to GBA deficiency
lead to dysregulation of EVs, which promotes the transfer of protein aggregates from cell to cell
and leads to faster progression of neurodegeneration. Understanding the mechanisms underlying
the prion-like propagation of protein aggregates has the potential to reveal novel therapeutic
targets that could slow or halt PD and other neurodegenerative diseases characterized by the
spread of pathogenic protein aggregation.

## Key facts

- **NIH application ID:** 10402005
- **Project number:** 3R01NS119897-01S1
- **Recipient organization:** SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
- **Principal Investigator:** Marie Ynez Davis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $39,835
- **Award type:** 3
- **Project period:** 2021-05-06 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10402005

## Citation

> US National Institutes of Health, RePORTER application 10402005, Investigating the role of lipid metabolism in protein aggregation and neurodegenerative disease progression (3R01NS119897-01S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10402005. Licensed CC0.

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