Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic

Todd Logan, Matthew J. Simon, Anil Rana, Gerald M. Cherf, Ankita Srivastava, Sonnet S. Davis, Ray Lieh Yoon Low, Chi Lu Chiu, Meng Fang, Fen Huang, Akhil Bhalla, Ceyda Llapashtica, Rachel Prorok, Michelle E. Pizzo, Meredith E.K. Calvert, Elizabeth W. Sun, Jennifer Hsiao-Nakamoto, Yashas Rajendra, Katrina W. Lexa, Devendra B. SrivastavaBettina van Lengerich, Junhua Wang, Yaneth Robles-Colmenares, Do Jin Kim, Joseph Duque, Melina Lenser, Timothy K. Earr, Hoang Nguyen, Roni Chau, Buyankhishig Tsogtbaatar, Ritesh Ravi, Lukas L. Skuja, Hilda Solanoy, Howard J. Rosen, Bradley F. Boeve, Adam L. Boxer, Hilary W. Heuer, Mark S. Dennis, Mihalis S. Kariolis, Kathryn M. Monroe, Laralynne Przybyla, Pascal E. Sanchez, Rene Meisner, Dolores Diaz, Kirk R. Henne, Ryan J. Watts, Anastasia G. Henry, Kannan Gunasekaran, Giuseppe Astarita, Jung H. Suh, Joseph W. Lewcock, Sarah L. DeVos, Gilbert Di Paolo

Research output: Contribution to journalArticlepeer-review


GRN mutations cause frontotemporal dementia (GRN-FTD) due to deficiency in progranulin (PGRN), a lysosomal and secreted protein with unclear function. Here, we found that Grn–/– mice exhibit a global deficiency in bis(monoacylglycero)phosphate (BMP), an endolysosomal phospholipid we identified as a pH-dependent PGRN interactor as well as a redox-sensitive enhancer of lysosomal proteolysis and lipolysis. Grn–/– brains also showed an age-dependent, secondary storage of glucocerebrosidase substrate glucosylsphingosine. We investigated a protein replacement strategy by engineering protein transport vehicle (PTV):PGRN—a recombinant protein linking PGRN to a modified Fc domain that binds human transferrin receptor for enhanced CNS biodistribution. PTV:PGRN rescued various Grn–/– phenotypes in primary murine macrophages and human iPSC-derived microglia, including oxidative stress, lysosomal dysfunction, and endomembrane damage. Peripherally delivered PTV:PGRN corrected levels of BMP, glucosylsphingosine, and disease pathology in Grn–/– CNS, including microgliosis, lipofuscinosis, and neuronal damage. PTV:PGRN thus represents a potential biotherapeutic for GRN-FTD.

Original languageEnglish (US)
Pages (from-to)4651-4668.e25
Issue number18
StatePublished - Sep 2 2021


  • GBA
  • LBPA
  • galectin-3
  • lipidomics
  • lipids
  • lipofuscin
  • lysobisphosphatidic acid
  • lysosome
  • metabolomics
  • neurodegenerative disease

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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