Gaucher disease (GD) is a genetic disease caused by mutations in the GBA1 gene which result in reduced enzymatic activity of ?-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 novel modifier of GD, provide new insight into the molecular events in the pathogenesis of GD, but could also lead to the development of novel biologics for treating GD, in particular neuropathic GD.

Public Health Relevance

The proposed studies will present a novel factor, or a new modifier of GCase, and provide a better understanding of pathogenesis of Gaucher Diseases. Identification of novel molecule and its derivative may also provide the basis for developing the novel therapeutic treatments in Gaucher Diseases, in particular the neuropathic Gaucher Diseases.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Therapeutic Approaches to Genetic Diseases Study Section (TAG)
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Morris, Jill A
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New York University
Schools of Medicine
New York
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