# The cause and effect of reduced ò-glucocerebrosidase activity in the setting of progranulin deficiency

> **NIH NIH F30** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $39,302

## Abstract

PROJECT SUMMARY
The objective of the proposed research project is to further understand how progranulin (GRN) and β-
glucocerebrosidase (GCase) interact and the implications of these interactions in frontotemporal dementia (FTD)
caused by progranulin mutations. Frontotemporal dementia is a leading cause of early-onset dementia, and loss-
of-function progranulin mutations are one of three main genetic causes. Progranulin is a secreted and lysosome-
resident glycoprotein, and deficiency causes lysosomal dysfunction in patients and in mice. Progranulin-boosting
therapies have promise for treating FTD-GRN, but delivery is an issue and the safety profile is unclear. This
underscores a critical need to continue to search for targeted therapeutics with known safety profiles. Thus, a
targeted therapy that reduces progranulin deficiency-induced lysosomal dysfunction may have therapeutic
benefits for preventing or delaying FTD-GRN.
In order to understand the underlying lysosomal dysfunction caused by progranulin deficiency, our lab has
characterized the activities of several lysosomal enzymes in the brains of FTD-GRN patients and progranulin-
deficient mice. We found decreased activity of neuronal GCase, a lysosomal enzyme, whereas other lysosomal
enzymes show increased activity. GCase is an interesting target because of its known involvement in
neurodegenerative disease, as GCase mutations are the leading genetic risk factor for Parkinson disease and
the monogenic cause of Gaucher disease, a lysosomal storage disease with neurodegenerative subtypes.
GCase deficiency in FTD-GRN appears to be due to an impairment in glycosylation causing GCase aggregation.
This proposal will determine if progranulin deficiency impairs GCase trafficking, resulting in decreased lysosomal
localization. The overarching hypothesis is that impaired progranulin-mediated GCase trafficking
contributes to lysosomal dysfunction and other deficits caused by progranulin deficiency. This proposal
will test the following two aims: (1) Determine how progranulin regulates trafficking of GCase and (2) Determine
if GCase deficits contribute to lysosomal dysfunction and other deficits caused by progranulin deficiency. More
work is needed to understand the specifics and effects of the progranulin-GCase interaction. I will first determine
the domain of progranulin responsible for GCase interaction and will then test the effects of this interaction on
GCase stability and lysosomal trafficking. I will then determine if increasing GCase is sufficient to reduce
lysosomal dysfunction and behavioral abnormalities in progranulin-deficient mice.
This proposal will facilitate my scientific and professional development by helping me: 1) improve competency
in rigorous experimental design and hypothesis testing, 2) refine known experimental techniques and develop
skills for translational research, and 3) gain experience presenting data to both scientific and lay audiences.

## Key facts

- **NIH application ID:** 10140562
- **Project number:** 1F30AG071114-01
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Nicholas Ryan Boyle
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $39,302
- **Award type:** 1
- **Project period:** 2021-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10140562

## Citation

> US National Institutes of Health, RePORTER application 10140562, The cause and effect of reduced ò-glucocerebrosidase activity in the setting of progranulin deficiency (1F30AG071114-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10140562. Licensed CC0.

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