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

Autor: Root J; Department of Pharmacology and Chemical Biology, Emory University, School of Medicine, Atlanta, GA 30322, USA.; Center for Neurodegenerative Disease, Emory University, School of Medicine, Atlanta, GA 30322, USA., Mendsaikhan A; Department of Pharmacology and Chemical Biology, Emory University, School of Medicine, Atlanta, GA 30322, USA.; Center for Neurodegenerative Disease, Emory University, School of Medicine, Atlanta, GA 30322, USA., Nandy S; Department of Pharmacology and Chemical Biology, Emory University, School of Medicine, Atlanta, GA 30322, USA.; Center for Neurodegenerative Disease, Emory University, School of Medicine, Atlanta, GA 30322, USA., Taylor G; Department of Pharmacology and Chemical Biology, Emory University, School of Medicine, Atlanta, GA 30322, USA.; Center for Neurodegenerative Disease, Emory University, School of Medicine, Atlanta, GA 30322, USA., Wang M; Department of Pharmacology and Chemical Biology, Emory University, School of Medicine, Atlanta, GA 30322, USA.; Center for Neurodegenerative Disease, Emory University, School of Medicine, Atlanta, GA 30322, USA., Araujo LT; Department of Pharmacology and Chemical Biology, Emory University, School of Medicine, Atlanta, GA 30322, USA.; Center for Neurodegenerative Disease, Emory University, School of Medicine, Atlanta, GA 30322, USA., Merino P; Department of Pharmacology and Chemical Biology, Emory University, School of Medicine, Atlanta, GA 30322, USA.; Center for Neurodegenerative Disease, Emory University, School of Medicine, Atlanta, GA 30322, USA., Ryu D; Department of Pharmacology and Chemical Biology, Emory University, School of Medicine, Atlanta, GA 30322, USA.; Center for Neurodegenerative Disease, Emory University, School of Medicine, Atlanta, GA 30322, USA., Holler C; Arkuda Therapeutics, 200 Arsenal Yards Blvd Suite 220, Watertown, MA 02472, USA., Thompson BM; Arkuda Therapeutics, 200 Arsenal Yards Blvd Suite 220, Watertown, MA 02472, USA., Astarita G; Arkuda Therapeutics, 200 Arsenal Yards Blvd Suite 220, Watertown, MA 02472, USA., Blain JF; Arkuda Therapeutics, 200 Arsenal Yards Blvd Suite 220, Watertown, MA 02472, USA., Kukar T; Department of Pharmacology and Chemical Biology, Emory University, School of Medicine, Atlanta, GA 30322, USA.; Center for Neurodegenerative Disease, Emory University, School of Medicine, Atlanta, GA 30322, USA.; Department of Neurology, Emory University, School of Medicine, Atlanta, GA 30322, USA.; Lead contact.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2023 Apr 18. Date of Electronic Publication: 2023 Apr 18.
DOI: 10.1101/2023.04.17.536004
Abstrakt: Progranulin (PGRN) deficiency is linked to neurodegenerative diseases including frontotemporal dementia, Alzheimer's disease, Parkinson's disease, and neuronal ceroid lipofuscinosis. Proper PGRN levels are critical to maintain brain health and neuronal survival, however the function of PGRN is not well understood. PGRN is composed of 7.5 tandem repeat domains, called granulins, and is proteolytically processed into individual granulins inside the lysosome. The neuroprotective effects of full-length PGRN are well-documented, but the role of granulins is still unclear. Here we report, for the first time, that expression of single granulins is sufficient to rescue the full spectrum of disease pathology in mice with complete PGRN deficiency ( Grn -/- ). Specifically, rAAV delivery of either human granulin-2 or granulin-4 to Grn -/- mouse brain ameliorates lysosome dysfunction, lipid dysregulation, microgliosis, and lipofuscinosis similar to full-length PGRN. These findings support the idea that individual granulins are the functional units of PGRN, likely mediate neuroprotection within the lysosome, and highlight their importance for developing therapeutics to treat FTD- GRN and other neurodegenerative diseases.
Competing Interests: DECLARATION OF INTERESTS C.H., B.M.T., G.A., and J-F.B. are full-time employees of Arkuda Therapeutics. Patent pending related to this work entitled “Methods to treat neurodegeneration with granulins” to C.H., G.T., T.K. All authors declare that they have no conflicts of interest with the contents of this article.
Databáze: MEDLINE