Network analysis of the progranulin-deficient mouse brain proteome reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations

• Type of Material: Article
• Authors: Meixiang Huang, Emory University; Erica Modeste, Emory University; Eric Dammer, Emory University; Paola Merino, Emory University; Georgia Taylor, Emory University; Duc M. Duong, Emory University; Qiudong Deng, Emory University; Christopher J. Holler, Emory University; Marla Gearing, Emory University; Dennis Dickson, Mayo Clinic; Nicholas Seyfried, Emory University; Thomas Kukar, Emory University
• Language: English
• Date: 2020-10-07
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2020
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s40478-020-01037-x
• Title of Journal or Parent Work: Acta Neuropathologica Communications
• Volume: 8
• Grant/Funding Information: Samples from the Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) study and the Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) study were obtained through the National Centralized Repository for Alzheimer Disease and Related Dementias (NCRAD), which receives government support under a cooperative agreement Grant (U24 AG21886) awarded by the National Institute on Aging (NIA), were used in this study. The Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) study receives support through a U.S Department of Health and Human Services (DHHS) and the National Institute of Neurological Disorders and Stroke (NINDS)/National Center for Advancing Translational Sciences (NCATS) Grant U54NS092089. The Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Study was made possible through the support of the U.S Department of Health and Human Services (DHHS) and the National Institute on Aging (NIA)/National Institute of Neurological Disorders and Stroke (NINDS) Grant U01AG045390. We thank the staff and investigators of the study as well as the participants and their families, whose help and participation made this work possible. Human biological samples and associated data were obtained from the Emory Neuropathology Core (P30 NS055077). This work was supported by P30-NS055077 to the Neuropathology/Histochemistry core of the Emory NINDS Neurosciences Core Facility, AG025688 to Emory’s Alzheimer’s Disease Research Center, an Emory University Research Committee Grant (T.K), National Institutes of Health (NIH) Grants (R01NS093362, R01NS105971), a New Vision Award (Donors Cure Foundation), an Emory Alzheimer's Disease Center Pilot Grant P50AG025688, the Alzheimer's Drug Discovery Foundation, the Association for Frontotemporal Degeneration (ADDF/AFTD), the Bluefield Project to Cure Frontotemporal Dementia, and the BrightFocus Foundation to TK.
• Keywords: Frontotemporal lobar degeneration (FTLD); Neurodegeneration; Proteomics; Frontotemporal dementia (FTD); Inflammation; Galectin-3; Lysosome; GPNMB; Progranulin (PGRN)
• Research Categories: Biology, Neuroscience; Chemistry, Biochemistry; Health Sciences, Pathology

Abstract

Heterozygous, loss-of-function mutations in the granulin gene (GRN) encoding progranulin (PGRN) are a common cause of frontotemporal dementia (FTD). Homozygous GRN mutations cause neuronal ceroid lipofuscinosis-11 (CLN11), a lysosome storage disease. PGRN is a secreted glycoprotein that can be proteolytically cleaved into seven bioactive 6 kDa granulins. However, it is unclear how deficiency of PGRN and granulins causes neurodegeneration. To gain insight into the mechanisms of FTD pathogenesis, we utilized Tandem Mass Tag isobaric labeling mass spectrometry to perform an unbiased quantitative proteomic analysis of whole-brain tissue from wild type (Grn+/+) and Grn knockout (Grn−/−) mice at 3- and 19-months of age. At 3-months lysosomal proteins (i.e. Gns, Scarb2, Hexb) are selectively increased indicating lysosomal dysfunction is an early consequence of PGRN deficiency. Additionally, proteins involved in lipid metabolism (Acly, Apoc3, Asah1, Gpld1, Ppt1, and Naaa) are decreased; suggesting lysosomal degradation of lipids may be impaired in the Grn−/− brain. Systems biology using weighted correlation network analysis (WGCNA) of the Grn−/− brain proteome identified 26 modules of highly co-expressed proteins. Three modules strongly correlated to Grn deficiency and were enriched with lysosomal proteins (Gpnmb, CtsD, CtsZ, and Tpp1) and inflammatory proteins (Lgals3, GFAP, CD44, S100a, and C1qa). We find that lysosomal dysregulation is exacerbated with age in the Grn−/− mouse brain leading to neuroinflammation, synaptic loss, and decreased markers of oligodendrocytes, myelin, and neurons. In particular, GPNMB and LGALS3 (galectin-3) were upregulated by microglia and elevated in FTD-GRN brain samples, indicating common pathogenic pathways are dysregulated in human FTD cases and Grn−/− mice. GPNMB levels were significantly increased in the cerebrospinal fluid of FTD-GRN patients, but not in MAPT or C9orf72 carriers, suggesting GPNMB could be a biomarker specific to FTD-GRN to monitor disease onset, progression, and drug response. Our findings support the idea that insufficiency of PGRN and granulins in humans causes neurodegeneration through lysosomal dysfunction, defects in autophagy, and neuroinflammation, which could be targeted to develop effective therapies.