# Development of a GBA p.E326K associated Parkinsons disease and Dementia with Lewy body mouse model

> **NIH NIH R03** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $81,000

## Abstract

Gaucher disease (GD), one of the most common autosomal recessive lysosomal storage disorders, is caused
by mutations in the Glucocerebrosidase (GBA) gene. The enzyme encoded by GBA, Gcase1, catalyzes the
conversion of glucosylceramide (GlcCer) to glucose and ceramide. The primary defect in GD is the
accumulation of GlcCer in lysosomes and is seen most prominently in macrophages. We and others have
shown that specific mutations in the GBA gene, in the heterozygous state, are a risk factor for Parkinson’s
disease (PD) and dementia with Lewy bodies (DLB). Functional studies have demonstrated an interaction
between α-synuclein and GBA protein and mutant GBA proteins can cause an increase in α-synuclein (SNCA)
levels and lysosomal dysfunction. Among the GBA variants associated with PD, p.E326K is one of the most
frequent. Interestingly, the GBA p.E326K variant is only involved in GD when it is found in the same allele (in
cis) with other ‘severe’ type mutations (e.g. p.L444P) and contributes to GD severity by further reducing
residual enzyme activity. Although biochemical observations have suggested that p.E326K is a ‘mild’ type loss
of function variant, this reduction in activity is clearly not severe enough to lead to a GD phenotype.
Understanding the mechanistic links between specific GBA mutations and PD is critical for developing targeted
therapeutic approaches. Currently, it is unclear how the GBA p.E326K mutation contributes to a neurological
phenotype and pathology in the brain. More recent studies suggest that ceramide metabolism and its
metabolites play a central role in disease pathogenesis of GBA-associated PD and DLB. We hypothesize that
the GBA p.E326K variant, contributes to disease by a mechanism involving an imbalance (increase) of other
metabolites in the ceramide metabolism pathway namely Glucosylsphingosine (GlcSph) and Sphingosine
(Sph) leading to α-synuclein aggregation and ER stress. Currently, therapeutic approaches to treat GBA
associated PD are limited to a glucosylceramide synthase inhibitor and a molecular chaperone, ambroxol
hydrochloride, both of which are currently in clinical trials. Development of a mouse model for the most
common GBA variant associated with PD, the GBA p.E326K variant, and determining the disease mechanism
may open up new avenues for therapeutic development targeting ASAH1 or GBA2 in the ceramide pathway
and could have a major impact on the field. The goal of this proposal is to develop and characterize a Gba
p.E326K mouse model that can be used for therapeutic development in future studies. we propose two specific
aims. Specific Aim 1 is to generate and characterize a Gba p.E326K mouse model of PD and DLB and Specific
Aim 2 is to determine whether overexpression of the human A30P α-synuclein (SNCA) transgene modifies
penetrance in Gba p.E326K mice and affects age of onset and progression of neurological symptoms.

## Key facts

- **NIH application ID:** 10011905
- **Project number:** 5R03NS113038-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** LORRAINE N CLARK
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $81,000
- **Award type:** 5
- **Project period:** 2019-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10011905

## Citation

> US National Institutes of Health, RePORTER application 10011905, Development of a GBA p.E326K associated Parkinsons disease and Dementia with Lewy body mouse model (5R03NS113038-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10011905. Licensed CC0.

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