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

Autor: Ryan J. Watts, Kathryn M. Monroe, Junhua Wang, Melina Lenser, Jennifer Hsiao-Nakamoto, Hoang Nguyen, Todd P. Logan, Do Jin Kim, Fen Huang, Ritesh Ravi, Gilbert Di Paolo, Anil Rana, Kannan Gunasekaran, Yaneth Robles-Colmenares, Gerald M. Cherf, Buyankhishig Tsogtbaatar, Ceyda Llapashtica, Kirk R. Henne, Hilda Solanoy, Pascal E. Sanchez, Yashas Rajendra, Mihalis Kariolis, Ray Lieh Yoon Low, Roni Chau, Laralynne Przybyla, Michelle E. Pizzo, Chi-Lu Chiu, Meng Fang, Anastasia G. Henry, Giuseppe Astarita, Mark S. Dennis, Adam L. Boxer, Sarah L. DeVos, Sonnet S. Davis, Hilary W. Heuer, René Meisner, Joseph W. Lewcock, Devendra B. Srivastava, Bradley F. Boeve, Meredith E. K. Calvert, Katrina W. Lexa, Rachel Prorok, Lukas L. Skuja, Dolores Diaz, Akhil Bhalla, Matthew Simon, Jung H. Suh, Ankita Srivastava, Timothy K. Earr, Howard J. Rosen, Joseph Duque, Bettina Van Lengerich, Elizabeth W. Sun
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Male
Neurodegenerative
Inbred C57BL
medicine.disease_cause
Medical and Health Sciences
Transgenic
Mice
neurodegenerative disease
Progranulins
Immunologic
Receptors
2.1 Biological and endogenous factors
Tissue Distribution
Gliosis
Aetiology
Receptors
Immunologic

lipofuscin
Alzheimer's Disease Related Dementias (ADRD)
Membrane Glycoproteins
Microglia
Transferrin
Brain
Biological Sciences
metabolomics
Cell biology
Frontotemporal Dementia (FTD)
medicine.anatomical_structure
Phenotype
Galectin-3
Frontotemporal Dementia
Neurological
Bone Morphogenetic Proteins
lysosome
GBA
Female
LBPA
Induced Pluripotent Stem Cells
Transferrin receptor
Mice
Transgenic

Endosomes
Biology
General Biochemistry
Genetics and Molecular Biology

Article
Lipofuscin
lipids
Rare Diseases
Lysosome
galectin-3
Receptors
Transferrin

Acquired Cognitive Impairment
medicine
Animals
Humans
Loss function
Inflammation
Biological Products
Macrophages
Neurosciences
Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD)
Lipid Metabolism
Brain Disorders
Lysosomal Storage Diseases
Mice
Inbred C57BL

Nerve Degeneration
lipidomics
Dementia
lysobisphosphatidic acid
Lysosomes
Glucocerebrosidase
Oxidative stress
Developmental Biology
Zdroj: Cell
Cell, vol 184, iss 18
Popis: 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.
Databáze: OpenAIRE
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