ASO-mediated knock-down of GPNMB in mutant-GRN and in Grn-deficient peripheral myeloid cells disrupts lysosomal function and immune responses
Our data herein reveal that GPNMB has a regulatory effect on multiple immune effector functions, including capping inflammation and immune responses in myeloid cells, potentially via secretion of its ECF. Therefore, in progranulin-deficient states, the marked upregulation in GPNMB transcript and protein may represent a compensatory mechanism to preserve lysosomal function in myeloid cells. These novel findings indicate that targeted depletion of GPNMB in FTD-GRN would not be a rational therapeutic strategy because it is likely to dysregulate important immune cell effector functions mediated by GPNMB. Specifically, our data indicate that therapeutic strategies inhibiting GPNMB levels and/or activity may worsen the effects of GRN deficiency.
Authors
- Julian Mark
- Malu Gámez Tansey (ORCID: https://orcid.org/0000-0002-1719-4708)
- Warren D. Hirst (ORCID: https://orcid.org/0000-0003-0389-8891)
- Drew A. Gillett
- Holly B. Kordasiewicz (ORCID: https://orcid.org/0009-0004-0945-0769)
- Rebecca Wallings (ORCID: https://orcid.org/0000-0003-3878-291X)
- Noelle K. Neighbarger (ORCID: https://orcid.org/0009-0007-6649-0988)
- Hannah A. Staley (ORCID: https://orcid.org/0009-0001-8284-6178)
- Savanna Mahn
Institutions
- Biogen (United States) (US)
- Ionis Pharmaceuticals (United States) (US)
- University of Florida Health (US)
- University of Florida (US)
- InterScience (United States) (US)
Publication Details
- Journal
- Molecular Neurodegeneration
- Published
- 2025-04-08
- DOI
- https://doi.org/10.1186/s13024-025-00829-w
- Citations
- 5
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 4.21
Funders
- Parkinson's Disease Foundation
- Biogen
- BrightFocus Foundation
- International Centre for Bamboo and Rattan
- National Institute of Neurological Disorders and Stroke