# Characterizing upstream regulators of glucosylceramide metabolism for Parkinson's disease and Lewy Body Dementia

> **NIH NIH R03** · CREIGHTON UNIVERSITY · 2021 · $145,500

## Abstract

Parkinson’s disease (PD)-associated dementia and Lewy Body Dementia (LBD) incidence is
high among the aged population with 1% of those over 60 and 4% of those over 80. Mutations in the
GBA gene represent one of the most common genetic risk factors for PD and LBD. GBA encodes the
lysosomal enzyme glucocerebrosidase (GCase) which converts glucosylceramide to ceramide and
glucose, and PD patients with GBA mutations have earlier onset of disease and greater cognitive
decline. Mutations in GBA leading to Parkinson’s lead to a reduction in GCase activity, and GCase
activity is also significantly decreased in the substantia nigra and anterior cingulate cortex in sporadic
PD and LBD cases, suggesting a critical role for GCase activity in the pathophysiology of PD and LBD.
Importantly, glucosylceramide has been shown to promote aggregation of alpha-synuclein, leading to
Lewy body formation. While there is no cure of PD or LBD, treatment is targeted primarily to improve
symptoms, including L-DOPA and other dopamine agonists. However, as neuronal loss within the
substantia nigra continues, the effectiveness of dopamine targeted therapies is greatly reduced.
Therefore, identifying mechanisms to increase GBA activity may be an ideal method for therapeutic
intervention for those patients harboring mutant GBA or reduced GCase activity. However, the
upstream mechanisms regulating GBA activity remain unknown. We recently discovered that the S-
adenosylmethionine (SAM) synthetase MAT2A may negatively regulate GBA activity thereby
suggesting that inhibition of MAT2A may serve as a novel mechanism to upregulate GCase activity and
provide a new treatment strategy for PD and LBD.
 Based on our preliminary data, we hypothesize that MAT2A negatively regulates GBA and
therefore targeting MAT2A for inhibition may restore GBA activity in individuals with PD and LBD
carrying mutations in GBA. We anticipate results in this study will define the molecular mechanism by
which MAT2A controls GBA to influence glucosylceramide levels which are intimately linked to PD and
LBD, assess whether reduced glucosylceramide in response to MAT2A inhibition will suppress alpha-
synuclein aggregation and toxicity, as well as to identify new candidate genes involved in this pathway
which could serve as additional potential therapeutic targets for PD and LBD.
 These studies will determine upstream regulatory mechanisms controlling glucosylceramide
metabolism contributing to PD and LBD in both GBA-associated PD as well as patients who have
altered GCase activity in the absence of GBA mutations. Furthermore, these studies will well serve as
proof-of-principle for targeting MAT2A as a novel PD and LBD therapeutic strategy.

## Key facts

- **NIH application ID:** 10111243
- **Project number:** 1R03AG070492-01
- **Recipient organization:** CREIGHTON UNIVERSITY
- **Principal Investigator:** Brian J. North
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $145,500
- **Award type:** 1
- **Project period:** 2021-01-15 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10111243

## Citation

> US National Institutes of Health, RePORTER application 10111243, Characterizing upstream regulators of glucosylceramide metabolism for Parkinson's disease and Lewy Body Dementia (1R03AG070492-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10111243. Licensed CC0.

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