Granulins rescue inflammation, lysosome dysfunction, lipofuscin, and neuropathology in a mouse model of progranulin deficiency
Open accessAbstract
Progranulin (PGRN) deficiency is linked to neurodegenerative diseases, including frontotemporal dementia (FTD), Alzheimer's disease, and Parkinson's disease. Proper PGRN levels are critical for brain health; however, the function of PGRN is unclear. PGRN is composed of 7.5 repeat domains, called granulins, and processed into granulins inside the lysosome. PGRN is beneficial for neuronal health, but the role of individual granulins is controversial and unclear. We find that the expression of single granulins broadly rescues disease pathology in Grn −/− mice. Adeno-associated virus (AAV)-mediated expression of human granulin-2/F, granulin-4/A, or PGRN in Grn −/− mouse brain ameliorates dysregulated lysosomal proteins and lipids, microgliosis, and lipofuscinosis. Mechanistically, granulins localize to lysosomes in Grn −/− mouse brains or fibroblasts. These data support the hypothesis that PGRN is a precursor to granulins, which share a beneficial function inside the lysosome to maintain lipid and protein homeostasis to prevent neurodegeneration. Thus, granulins are potential therapeutics to treat FTD- GRN and related diseases.
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BMP is an anionic, late-endosome/lysosome-specific glycerophospholipid that is reduced in several neurodegenerative disorders, including GRN-FTD.
“BMP is an anionic, late-endosome/lysosome-specific glycerophospholipid that is reduced in several neurodegenerative disorders, including GRN-FTD. BMP stimulates lysosomal lipases and promotes cholesterol egress into the cytosol.137”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [137]
The Results section, “Lysosomal lipid dysregulation is rescued by a single GRN” (page unavailable), calls BMP an atypical endo-lysosomal lipid and reports reduced BMP in Grn−/− mouse brains. It does not establish that BMP is anionic or specific to late endosomes and lysosomes, or that BMP is reduced in several human neurodegenerative disorders, including FTD-GRN. (LLM, conf=0.86)
Experimental — accuracy not yet measuredBMP stimulates lysosomal lipases and promotes cholesterol egress into the cytosol.
“BMP is an anionic, late-endosome/lysosome-specific glycerophospholipid that is reduced in several neurodegenerative disorders, including GRN-FTD. BMP stimulates lysosomal lipases and promotes cholesterol egress into the cytosol.137”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [137]
The Results section, “Lysosomal lipid dysregulation is rescued by a single GRN” (page unavailable), reports reduced BMP in Grn-deficient mouse brains and restoration after hGRN4 or hPGRN expression. It does not address whether BMP stimulates lysosomal lipases or promotes cholesterol egress into the cytosol; searches for those mechanisms found no supporting passage. (LLM, conf=0.76)
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Self-citationJohnson, M. A., Nuckols, T. A., Merino, P., Bagchi, P., Nandy, S., Root, J. T., Taylor, G., Seyfried, N. T., & Kukar, T. L. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102135 · Cited by 5 · see citing works
Self-citationDiscovery of oxazoline enhancers of cellular progranulin release
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Self-citationBlain, J., Chen, A. Y.-P., Brand, M. A., Lanter, J. C., Holler, C. J., Brendel, J. K., Koenig, G., Burnett, D. A., & Hurst, R. S. (2022) · Alzheimer s & Dementia · doi:10.1002/alz.061924 · Cited by 1 · see citing works
Self-citation
Flagged first, then by citations
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Research works printed but not linked: 1
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Self-citation
- Authors
- Root, J., Mendsaikhan, A., Taylor, G., Merino, P., Nandy, S., Wang, M., Araujo, L. T., Ryu, D., Holler, C., Thompson, B. M., Astarita, G., Blain, J.-F., & Kukar, T.
- Affiliations
- Emory University (US)
- Corresponding author
- Kukar, Thomas
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2024-12
- Volume
- 43
- Issue
- 12
- Pages
- 114985
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC11773623
- OpenAlex
- W4404514683
- Cited by
- 39
- References
- 97
- Citations by year
- 2026: 18 · 2025: 21
- FWCI
- 10.43
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Cancer Institute (P30CA138292)
- National Institute on Aging (RF1AG079318)
- School of Medicine, Emory University (F31NS117129)
- BrightFocus Foundation
- Alzheimer's Drug Discovery Foundation
- Association for Frontotemporal Degeneration
- National Institute of Neurological Disorders and Stroke (R01NS105971)
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- progranulin, granulin, progranulin deficiency, frontotemporal dementia, lysosomal dysfunction, lipofuscin, microglial activation, neurodegeneration, lysosomes, AAV gene therapy, Parkinson's disease, Alzheimer's disease
- MeSH terms
- Progranulins, Granulins, Animals, Brain, Disease Models, Animal, Humans, Inflammation, Lipofuscin, Lysosomes, Mice, Inbred C57BL, Mice, Knockout, Mice, Frontotemporal Dementia
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