# Progranulin: A Novel Gene in Gaucher Diseases

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $479,069

## Abstract

Project Summary
Gaucher disease (GD) is a genetic disease caused by mutations in the GBA1 gene which result in reduced
enzymatic activity of β-glucocerebrosidase (GCase); however, patients with the same GCase mutations may
have significant variably in disease presentation, ranging from a life-threatening manifestation to almost
asymptomatic. It is believed that the modifier genes are responsible for the extraordinarily diverse phenotypes
among patients harboring identical GBA1 mutations. Thus, identification of new modifier genes in GD will
provide invaluable information in understanding the pathogenesis of GD and in searching for novel diagnostic
and therapeutic targets for GD. Our previous report that progranulin (PGRN) is therapeutic against
inflammatory arthritis (Tang, et al. Science, 2011) prompted us to determine whether PGRN also played a role
in lung inflammation using ovalbumin (OVA)-challenged asthma model, which led to the unexpected discovery
of GRN (the gene encoding PGRN) as a novel gene in GD. PGRN null mice display typical features of GD,
including “wrinkled tissue paper” appearance of Gaucher cells in multiple organs, and tubular-like lysosome
transformation in macrophages. In addition, serum PGRN levels of GD patients are significantly lower when
compared to healthy controls, and lower PGRN level was significantly associated with the GRN variants
identified in GD patients (Jian, et al, EBioMedicine, 2016a). PGRN binds directly to GCase, and its deficiency
results in aggregation in the cytoplasm and defects in the lysosomal localization of GCase. Additionally, 98 C-
terminal amino acids of PGRN, referred to as Pcgin, are required and sufficient for the binding to GCase. Pcgin
effectively ameliorates the disease phenotype in GD patient fibroblasts and OVA-challenged GD model (Jian,
et al, EBioMedicine, 2016b). There is an urgent unmet medical need for treating neuropathic GD, since current
enzyme replacement therapy for GD cannot penetrate into brain. Excitingly, our preliminary data revealed that
Pcgin could cross blood brain barrier and might be also therapeutic against neuropathic GD. In an effort to
elucidate the molecular mechanism underlying PGRN- and Pcgin-mediated therapeutic effect against GD, we
performed an unbiased proteomics screen, which led to the isolation of protein disulfide-isomerase A3 (PDIA3)
as a PGRN and Pcgin co-bound molecule. In addition, loss of PDIA3 abolished Pcgin's therapeutic effects in
GD patient fibroblasts. The hypothesis of this application is that PGRN is a novel modifier in GD and its
derivative Pcgin is therapeutic against GD. The Specific Aims are: (1) To determine the therapeutic role of
PGRN and its derivative Pcgin in GD, in particular against neuropathic GD; and (2) To elucidate the cellular
and molecular mechanisms by which PGRN and Pcgin regulate GCase and GD, with special focus on their
interactions with PDIA3 in GD. Completion of the proposed research will not only present PGRN as a...

## Key facts

- **NIH application ID:** 10251862
- **Project number:** 5R01NS103931-05
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Chuanju Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $479,069
- **Award type:** 5
- **Project period:** 2017-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10251862

## Citation

> US National Institutes of Health, RePORTER application 10251862, Progranulin: A Novel Gene in Gaucher Diseases (5R01NS103931-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10251862. Licensed CC0.

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