Granulins rescue inflammation, lysosome dysfunction, lipofuscin, and neuropathology in a mouse model of progranulin deficiency.

IF 7.5 1区生物学 Q1 CELL BIOLOGY Cell reports Pub Date : 2024-12-24 Epub Date: 2024-11-19 DOI:10.1016/j.celrep.2024.114985

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

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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.

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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。

Progranulin（PGRN）缺乏症与神经退行性疾病有关，包括额颞叶痴呆症（FTD）、阿尔茨海默病和帕金森病。适当的 PGRN 水平对大脑健康至关重要；然而，PGRN 的功能尚不清楚。PGRN 由 7.5 个重复结构域（称为粒蛋白）组成，并在溶酶体内加工成粒蛋白。PGRN 有利于神经元的健康，但单个颗粒蛋白的作用却存在争议且不明确。我们发现，表达单个颗粒蛋白可广泛拯救 Grn-/- 小鼠的疾病病理。腺相关病毒（AAV）介导的人粒细胞素-2/F、粒细胞素-4/A或PGRN在Grn-/-小鼠脑中的表达可改善溶酶体蛋白和脂质失调、小胶质细胞增多症和脂褐质沉着症。从机理上讲，粒蛋白会定位到 Grn-/- 小鼠大脑或成纤维细胞中的溶酶体。这些数据支持 PGRN 是粒蛋白前体的假设，粒蛋白在溶酶体内具有维持脂质和蛋白质平衡以防止神经变性的有益功能。因此，粒蛋白是治疗 FTD-GRN 及相关疾病的潜在疗法。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

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.