Progranulin as a therapeutic target in neurodegenerative diseases
Open accessAbstract
Progranulin (PGRN, encoded by the GRN gene) plays a key role in the development, survival, function, and maintenance of neurons and microglia in the mammalian brain. It regulates lysosomal biogenesis, inflammation, repair, stress response, and aging. GRN loss-of-function mutations cause neuronal ceroid lipofuscinosis or frontotemporal dementia-GRN (FTD-GRN) in a gene dosage-dependent manner. Mutations that reduce PGRN levels increase the risk for developing Alzheimer's disease, Parkinson's disease, and limbic-predominant age-related transactivation response DNA-binding protein 43 encephalopathy, as well as exacerbate the progression of amyotrophic lateral sclerosis (ALS) and FTD caused by the hexanucleotide repeat expansion in the C9orf72 gene. Elevating and/or restoring PGRN levels is an attractive therapeutic strategy and is being investigated for neurodegenerative diseases through multiple mechanisms of action.
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PGRN overexpression is protective in animal models of AD.
“PGRN overexpression is protective in animal models of AD.547”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [547]
AL001, a human monoclonal antibody that blocks sortilin-PGRN interaction to prevent degradation of PGRN, is being investigated in a Phase II study in ALS-C9orf72.
“Given the importance of PGRN in ALS development, AL001, a human monoclonal antibody that blocks the sortilin-PGRN interaction to prevent the degradation of PGRN, is currently being investigated in a Phase II study to evaluate its safety, pharmacokinetics, and pharmacodynamics in ALS-C9orf72.547”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [547]
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Role of neuroinflammation in neurodegeneration development
Zhang, W., Xiao, D., Mao, Q., & Xia, H. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01486-5 · Cited by 1,668 · see citing works
“PGRN overexpression is protective in animal models of AD.(547) Small molecule like ZAP2006 and monoclonal antibody like AL101 that can enhance the expression of PGRN have been developed and undergoing clinical trials for the treatment of AD (clinicaltrials.”
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- Authors
- Rhinn, H., Tatton, N., McCaughey, S., Kurnellas, M., & Rosenthal, A.
- Affiliations
- Alector (United States) (US)
- Corresponding author
- Rosenthal, Arnon
- Venue
- Trends in Pharmacological Sciences
- Publisher
- Elsevier BV
- Published
- 2022-08
- Volume
- 43
- Issue
- 8
- Pages
- 641-652
- ISSN
- 0165-6147 (ISSN-L)
- OpenAlex
- W4206610489
- Cited by
- 208
- References
- 8
- Citations by year
- 2026: 43 · 2025: 68 · 2024: 37 · 2023: 45 · 2022: 15
- FWCI
- 5.94
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Trends in Pharmacological Sciences (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- progranulin, GRN gene, neurodegenerative diseases, therapeutic target, neuronal ceroid lipofuscinosis, frontotemporal dementia, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, C9orf72 repeat expansion, lysosomal biogenesis, microglia
- MeSH terms
- Progranulins, Humans, Mutation, Microglia, Neurodegenerative Diseases, Frontotemporal Dementia
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