Granulins Rescue Inflammation, Lysosome Dysfunction, Lipofuscin, and Neuropathology in a Mouse Model of Progranulin Deficiency

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2024 Nov 20

PMID 39565694

Authors

Jessica Root

Anarmaa Mendsaikhan

Georgia Taylor

Paola Merino

Srijita Nandy

Minzheng Wang

Ludmilla Troiano Araujo

Danny Ryu

Christopher Holler

Bonne M Thompson

Giuseppe Astarita

Jean-Francois Blain

Thomas Kukar

Affiliations

Soon will be listed here.

Abstract

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.

References

Holler C, Taylor G, Deng Q, Kukar T . Intracellular Proteolysis of Progranulin Generates Stable, Lysosomal Granulins that Are Haploinsufficient in Patients with Frontotemporal Dementia Caused by Mutations. eNeuro. 2017; 4(4). PMC: 5562298. DOI: 10.1523/ENEURO.0100-17.2017. View

Grant B, Rodrigues A, ElSawy K, McCammon J, Caves L . Bio3d: an R package for the comparative analysis of protein structures. Bioinformatics. 2006; 22(21):2695-6. DOI: 10.1093/bioinformatics/btl461. View

Hinderer C, Miller R, Dyer C, Johansson J, Bell P, Buza E . Adeno-associated virus serotype 1-based gene therapy for FTD caused by GRN mutations. Ann Clin Transl Neurol. 2020; 7(10):1843-1853. PMC: 7545603. DOI: 10.1002/acn3.51165. View

Khrouf W, Saracino D, Rucheton B, Houot M, Clot F, Rinaldi D . Plasma lysosphingolipids in GRN-related diseases: Monitoring lysosomal dysfunction to track disease progression. Neurobiol Dis. 2023; 181:106108. DOI: 10.1016/j.nbd.2023.106108. View

Lui H, Zhang J, Makinson S, Cahill M, Kelley K, Huang H . Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation. Cell. 2016; 165(4):921-35. PMC: 4860138. DOI: 10.1016/j.cell.2016.04.001. View

Xu H, Tan L, Wan Y, Tan M, Zhang W, Zheng Z . PGRN Is Associated with Late-Onset Alzheimer's Disease: a Case-Control Replication Study and Meta-analysis. Mol Neurobiol. 2016; 54(2):1187-1195. DOI: 10.1007/s12035-016-9698-4. View

Katsumata Y, Shade L, Hohman T, Schneider J, Bennett D, Farfel J . Multiple gene variants linked to Alzheimer's-type clinical dementia via GWAS are also associated with non-Alzheimer's neuropathologic entities. Neurobiol Dis. 2022; 174:105880. PMC: 9641973. DOI: 10.1016/j.nbd.2022.105880. View

Salazar D, Butler V, Argouarch A, Hsu T, Mason A, Nakamura A . The Progranulin Cleavage Products, Granulins, Exacerbate TDP-43 Toxicity and Increase TDP-43 Levels. J Neurosci. 2015; 35(25):9315-28. PMC: 4478251. DOI: 10.1523/JNEUROSCI.4808-14.2015. View

Uhlen M, Fagerberg L, Hallstrom B, Lindskog C, Oksvold P, Mardinoglu A . Proteomics. Tissue-based map of the human proteome. Science. 2015; 347(6220):1260419. DOI: 10.1126/science.1260419. View

10.

Ahmed Z, Sheng H, Xu Y, Lin W, Innes A, Gass J . Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggest a role for progranulin in successful aging. Am J Pathol. 2010; 177(1):311-24. PMC: 2893674. DOI: 10.2353/ajpath.2010.090915. View

11.

Kessenbrock K, Frohlich L, Sixt M, Lammermann T, Pfister H, Bateman A . Proteinase 3 and neutrophil elastase enhance inflammation in mice by inactivating antiinflammatory progranulin. J Clin Invest. 2008; 118(7):2438-47. PMC: 2430496. DOI: 10.1172/JCI34694. View

12.

Lee C, Stankowski J, Chew J, Cook C, Lam Y, Almeida S . The lysosomal protein cathepsin L is a progranulin protease. Mol Neurodegener. 2017; 12(1):55. PMC: 5526245. DOI: 10.1186/s13024-017-0196-6. View

13.

Marian O, Teo J, Lee J, Song H, Kwok J, Landin-Romero R . Disrupted myelin lipid metabolism differentiates frontotemporal dementia caused by GRN and C9orf72 gene mutations. Acta Neuropathol Commun. 2023; 11(1):52. PMC: 10041703. DOI: 10.1186/s40478-023-01544-7. View

14.

Lee M, Chen T, Cheng T, Chiu M . rs5848 variant of progranulin gene is a risk of Alzheimer's disease in the Taiwanese population. Neurodegener Dis. 2011; 8(4):216-20. DOI: 10.1159/000322538. View

15.

Logan T, Simon M, Rana A, Cherf G, Srivastava A, Davis S . Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic. Cell. 2021; 184(18):4651-4668.e25. PMC: 8489356. DOI: 10.1016/j.cell.2021.08.002. View

16.

Ward M, Chen R, Huang H, Ludwig C, Telpoukhovskaia M, Taubes A . Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis. Sci Transl Med. 2017; 9(385). PMC: 5526610. DOI: 10.1126/scitranslmed.aah5642. View

17.

L Petkau T, Neal S, Orban P, MacDonald J, Hill A, Lu G . Progranulin expression in the developing and adult murine brain. J Comp Neurol. 2010; 518(19):3931-47. DOI: 10.1002/cne.22430. View

18.

Lang I, Fullsack S, Wajant H . Lack of Evidence for a Direct Interaction of Progranulin and Tumor Necrosis Factor Receptor-1 and Tumor Necrosis Factor Receptor-2 From Cellular Binding Studies. Front Immunol. 2018; 9:793. PMC: 5925078. DOI: 10.3389/fimmu.2018.00793. View

19.

Staudt C, Puissant E, Boonen M . Subcellular Trafficking of Mammalian Lysosomal Proteins: An Extended View. Int J Mol Sci. 2016; 18(1). PMC: 5297682. DOI: 10.3390/ijms18010047. View

20.

Lamprecht M, Sabatini D, Carpenter A . CellProfiler: free, versatile software for automated biological image analysis. Biotechniques. 2007; 42(1):71-5. DOI: 10.2144/000112257. View