Granulins rescue inflammation, lysosome dysfunction, lipofuscin, and neuropathology in a mouse model of progranulin deficiency
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
Affiliations
Jessica Root
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
Anarmaa Mendsaikhan
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
Georgia Taylor
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
Paola Merino
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
Srijita Nandy
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
Minzheng Wang
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
Ludmilla Troiano Araujo
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
Danny Ryu
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
Christopher Holler
Arkuda Therapeutics, 200 Arsenal Yards Blvd., Suite 220, Watertown, MA 02472, USA
Bonne M. Thompson
Arkuda Therapeutics, 200 Arsenal Yards Blvd., Suite 220, Watertown, MA 02472, USA
Giuseppe Astarita
Arkuda Therapeutics, 200 Arsenal Yards Blvd., Suite 220, Watertown, MA 02472, USA
Jean-François Blain
Arkuda Therapeutics, 200 Arsenal Yards Blvd., Suite 220, Watertown, MA 02472, USA
Thomas Kukar
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; Corresponding author
Summary: 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.
