Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic
Open accessAbstract
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.
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SCARB2 has been identified in several PD risk genome-wide association studies.
“SCARB2 has been identified in several PD risk genome-wide association studies (GWAS).100–103”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [101]
The Introduction discusses GBA-linked Parkinson’s disease, and the References list a Parkinson’s disease GWAS meta-analysis, but neither passage says that SCARB2 was identified in several PD risk GWAS. Searches for SCARB2 and LIMP-2 found no passage addressing that claim in our copy. (LLM, conf=0.72)
Experimental — accuracy not yet measuredMutations in GRN are associated with abnormal tau protein phosphorylation.
“gene mutations in the premature ageing proteins PSEN1, PSEN2 [138,139], and GRN [140,141] have been shown to be associated with abnormal tau protein phosphorylation”
From Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review (2024) · cites this paper as [141]
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“For example, gene mutations in the premature ageing proteins PSEN1, PSEN2 [138,139], and GRN [140,141] have been shown to be associated with abnormal tau protein phosphorylation, which promotes the abnormal aggregation of tau protein, ultimately leading to the onset and development of…”
BackgroundTransferrin receptor-targeted anti-amyloid antibody enhances brain delivery and mitigates ARIA.
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- Authors
- Logan, T., Simon, M. J., Rana, A., Cherf, G. M., Srivastava, A., Davis, S. S., Low, R. L. Y., Chiu, C.-L., Fang, M., Huang, F., Bhalla, A., Llapashtica, C., Prorok, R., Pizzo, M. E., Calvert, M. E. K., Sun, E. W., Hsiao-Nakamoto, J., Rajendra, Y., Lexa, K. W., Srivastava, D. B., van Lengerich, B., Wang, J., Robles-Colmenares, Y., Kim, D. J., Duque, J., Lenser, M., Earr, T. K., Nguyen, H., Chau, R., Tsogtbaatar, B., Ravi, R., Skuja, L. L., Solanoy, H., Rosen, H. J., Boeve, B. F., Boxer, A. L., Heuer, H. W., Dennis, M. S., Kariolis, M. S., Monroe, K. M., Przybyla, L., Sanchez, P. E., Meisner, R., Diaz, D., Henne, K. R., Watts, R. J., Henry, A. G., Gunasekaran, K., Astarita, G., Suh, J. H., Lewcock, J. W., DeVos, S. L., & Di Paolo, G.
- Affiliations
- Denali Therapeutics (United States) (US)
- University of California, San Francisco (US)
- Mayo Clinic (US)
- Georgetown University (US)
- Corresponding author
- DeVos, Sarah L.
- ORCID
- Logan, Todd
- Simon, Matthew J.
- Cherf, Gerald M.
- Srivastava, Ankita
- Davis, Sonnet S.
- Low, Ray Lieh Yoon
- Fang, Meng
- Huang, Fen
- Prorok, Rachel
- Pizzo, Michelle E.
- Calvert, Meredith E.K.
- Sun, Elizabeth W.
- Rajendra, Yashas
- Lexa, Katrina W.
- Wang, Junhua
- Kim, Do Jin
- Duque, Joseph
- Earr, Timothy K.
- Nguyen, Hoang
- Chau, Roni
- Tsogtbaatar, Buyankhishig
- Ravi, Ritesh
- Skuja, Lukas L.
- Solanoy, Hilda
- Rosen, Howard J.
- Boeve, Bradley F.
- Boxer, Adam L.
- Heuer, Hilary W.
- Dennis, Mark S.
- Kariolis, Mihalis S.
- Monroe, Kathryn M.
- Przybyla, Laralynne
- Sanchez, Pascal E.
- Diaz, Dolores
- Henne, Kirk R.
- Watts, Ryan J.
- Henry, Anastasia G.
- Gunasekaran, Kannan
- Astarita, Giuseppe
- Suh, Jung H.
- Lewcock, Joseph W.
- DeVos, Sarah L.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2021-09
- Volume
- 184
- Issue
- 18
- Pages
- 4651-4668.e25
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC8489356
- OpenAlex
- W3195683533
- Cited by
- 233
- References
- 74
- Citations by year
- 2026: 42 · 2025: 55 · 2024: 55 · 2023: 47 · 2022: 32 · 2021: 2
- FWCI
- 22.15
- Type
- journal article
- Language
- en
- Update notices
- erratum (2024-03-14)
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 366 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (R01AG031278)
- National Institute of Neurological Disorders and Stroke (U54NS092089)
- Association for Frontotemporal Degeneration
- National Center for Advancing Translational Sciences
- National Institute on Aging (U24 AG021886, U19AG063911, U01 AG045390)
- Eisai
- Rainwater Charitable Foundation
- Eli Lilly and Company
- Topics
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- progranulin, GRN mutations, frontotemporal dementia, lysosomal storage disease, bis(monoacylglycero)phosphate, glucosylsphingosine, protein replacement therapy, transferrin receptor, microglia, lysosomal dysfunction, oxidative stress, lipofuscinosis, microglial activation, lipolysis, lipophagy
- MeSH terms
- Progranulins, Animals, Biological Products, Brain, Female, Gliosis, Humans, Inflammation, Lipofuscin, Lysosomes, Macrophages, Male, Membrane Glycoproteins, Mice, Inbred C57BL, Mice, Transgenic, Nerve Degeneration, Phenotype, Receptors, Immunologic, Receptors, Transferrin, Endosomes, Tissue Distribution, Lysosomal Storage Diseases, Microglia, Bone Morphogenetic Proteins, Lipid Metabolism, Mice, Induced Pluripotent Stem Cells, Frontotemporal Dementia
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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