Lysosomal functions of progranulin and implications for treatment of frontotemporal dementia
Open accessAbstract
Loss-of-function heterozygous mutations in GRN, the gene encoding progranulin (PGRN), were identified in patients with frontotemporal lobar degeneration (FTLD) almost two decades ago and are generally linked to reduced PGRN protein expression levels. Although initial characterization of PGRN function primarily focused on its role in extracellular signaling as a secreted protein, more recent studies revealed critical roles of PGRN in regulating lysosome function, including proteolysis and lipid degradation, consistent with its lysosomal localization. Emerging from these studies is the notion that PGRN regulates glucocerebrosidase activity via direct chaperone activities and via interaction with prosaposin (i.e., a key regulator of lysosomal sphingolipid-metabolizing enzymes), as well as with the anionic phospholipid bis(monoacylglycero)phosphate. This emerging lysosomal biology of PGRN identified novel and promising opportunities in therapeutic discovery as well as biomarker development.
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GRN encodes the lysosomal protein progranulin related to neurodegenerative diseases.
“GRN encodes the lysosomal protein progranulin related to neurodegenerative diseases50.”
From PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia (2025) · cites this paper as [50]
Lipofuscin is a key pathology in neuronal ceroid lipofuscinosis and GRN-linked frontotemporal dementia.
“While lipofuscin is key pathology in neuronal ceroid lipofuscinosis and GRN-linked frontotemporal dementia”
From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [70]
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Mechanisms of autophagy–lysosome dysfunction in neurodegenerative diseases
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“5d), two of which are related to lysosomal function: MCOLN1 is a ROS sensor in lysosomes regulating autophagy 49 , and GRN encodes the lysosomal protein progranulin related to neurodegenerative diseases 50 .”
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- Authors
- Simon, M. J., Logan, T., DeVos, S. L., & Di Paolo, G.
- Affiliations
- Denali Therapeutics (United States) (US)
- Venue
- Trends in Cell Biology
- Publisher
- Elsevier BV
- Published
- 2023-04
- Volume
- 33
- Issue
- 4
- Pages
- 324-339
- ISSN
- 0962-8924 (ISSN-L)
- OpenAlex
- W4304987274
- Cited by
- 94
- References
- 8
- Citations by year
- 2026: 18 · 2025: 23 · 2024: 28 · 2023: 23 · 2022: 2
- FWCI
- 2.62
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Trends in Cell Biology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Denali Therapeutics (DNL593, NCT05262023)
- 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, frontotemporal lobar degeneration, lysosomal function, glucocerebrosidase, chaperone activity, prosaposin, sphingolipid metabolism, bis(monoacylglycero)phosphate, proteolysis, lipid degradation, biomarkers, therapeutic target
- MeSH terms
- Progranulins, Humans, Lysosomes, Intercellular Signaling Peptides and Proteins, Frontotemporal Lobar Degeneration, Frontotemporal Dementia
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