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-François Blain, Thomas Kukar
{"title":"粒蛋白能挽救原粒蛋白缺乏症小鼠模型中的炎症、溶酶体功能障碍、脂褐素和神经病理学。","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-François Blain, Thomas Kukar","doi":"10.1016/j.celrep.2024.114985","DOIUrl":null,"url":null,"abstract":"<p><p>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<sup>-/-</sup> mice. Adeno-associated virus (AAV)-mediated expression of human granulin-2/F, granulin-4/A, or PGRN in Grn<sup>-/-</sup> mouse brain ameliorates dysregulated lysosomal proteins and lipids, microgliosis, and lipofuscinosis. Mechanistically, granulins localize to lysosomes in Grn<sup>-/-</sup> 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.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"43 12","pages":"114985"},"PeriodicalIF":7.5000,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11773623/pdf/","citationCount":"0","resultStr":"{\"title\":\"Granulins rescue inflammation, lysosome dysfunction, lipofuscin, and neuropathology in a mouse model of progranulin deficiency.\",\"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-François Blain, Thomas Kukar\",\"doi\":\"10.1016/j.celrep.2024.114985\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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<sup>-/-</sup> mice. Adeno-associated virus (AAV)-mediated expression of human granulin-2/F, granulin-4/A, or PGRN in Grn<sup>-/-</sup> mouse brain ameliorates dysregulated lysosomal proteins and lipids, microgliosis, and lipofuscinosis. Mechanistically, granulins localize to lysosomes in Grn<sup>-/-</sup> 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.</p>\",\"PeriodicalId\":9798,\"journal\":{\"name\":\"Cell reports\",\"volume\":\"43 12\",\"pages\":\"114985\"},\"PeriodicalIF\":7.5000,\"publicationDate\":\"2024-12-24\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11773623/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell reports\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1016/j.celrep.2024.114985\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/11/19 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell reports","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.celrep.2024.114985","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/11/19 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Granulins rescue inflammation, lysosome dysfunction, lipofuscin, and neuropathology in a mouse model of progranulin deficiency.
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.
期刊介绍：
Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted.
The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership.
The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.
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