ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2019
Genetic Regulation of Neuronal Progranulin Reveals a Critical Role for the Autophagy-Lysosome Pathway.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers, 1 of them a synthesis that pooled it.
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Who cites it
35 citing papers in PubMed, 1 synthesis or guideline pooled it, 56 citations in OpenAlex.
- Neurodevelopmental Clues to Neurodegeneration.Pediatric neurology · 2021Pooled it
- Wild-typemedRxiv : the preprint server for health sciences · 2026Article
- Progranulin promotes glioma progression via interaction with cathepsin D and serves as a diagnostic and prognostic biomarker.Discover oncology · 2026Article
- Reduction of sphingomyelinase activity associated with progranulin deficiency and frontotemporal dementia.Neurobiology of disease · 2025Article
- The role of autophagy in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).Autophagy reports · 2025Review
- Progranulin enhances the engraftment of transplanted human iPS cell-derived cerebral neurons.Stem cells translational medicine · 2024Article
- Alzheimer's disease: from early pathogenesis to novel therapeutic approaches.Metabolic brain disease · 2024Review
- Benzoxazole-derivatives enhance progranulin expression and reverse the aberrant lysosomal proteome caused by GRN haploinsufficiency.Nature communications · 2024Article
- Regulation of extracellular progranulin in medial prefrontal cortex.Neurobiology of disease · 2023Article
- The influence of NQO2 on the dysfunctional autophagy and oxidative stress induced in the hippocampus of rats and in SH-SY5Y cells by fluoride.CNS neuroscience & therapeutics · 2023Article
- Progranulin is an FMRP target that influences macroorchidism but not behaviour in a mouse model of Fragile X Syndrome.Current research in neurobiology · 2023Article
- Peroxisomal defects in microglial cells induce a disease-associated microglial signature.Frontiers in molecular neuroscience · 2023Article
- Charge and redox states modulate granulin-TDP-43 coacervation toward phase separation or aggregation.Biophysical journal · 2022Article
- Review
- Small molecule C381 targets the lysosome to reduce inflammation and ameliorate disease in models of neurodegeneration.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- The spectrum of neurodevelopmental, neuromuscular and neurodegenerative disorders due to defective autophagy.Autophagy · 2022Article
- Progranulin mediates immune evasion of pancreatic ductal adenocarcinoma through regulation of MHCI expression.Nature communications · 2022Article
- Analysis of the Biomarkers for Neurodegenerative Diseases in Aged Progranulin Deficient Mice.International journal of molecular sciences · 2022Article
- The Interplay Between Autophagy and RNA Homeostasis: Implications for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.Frontiers in cell and developmental biology · 2022Review
- Cell Non-autonomous Proteostasis Regulation in Aging and Disease.Frontiers in neuroscience · 2022Review
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Deficient progranulin levels cause dose-dependent neurological syndromes: haploinsufficiency leads to frontotemporal lobar degeneration (FTLD) and nullizygosity produces adult-onset neuronal ceroid lipofuscinosis. Mechanisms controlling progranulin levels are largely unknown. To better understand progranulin regulation, we performed a genome-wide RNAi screen using an ELISA-based platform to discover genes that regulate progranulin levels in neurons. We identified 830 genes that raise or lower progranulin levels by at least 1.5-fold in Neuro2a cells. When inhibited by siRNA or some by submicromolar concentrations of small-molecule inhibitors, 33 genes of the druggable genome increased progranulin levels in mouse primary cortical neurons; several of these also raised progranulin levels in FTLD model mouse neurons. "Hit" genes regulated progranulin by transcriptional or posttranscriptional mechanisms. Pathway analysis revealed enrichment of hit genes from the autophagy-lysosome pathway (ALP), suggesting a key role for this pathway in regulating progranulin levels. Progranulin itself regulates lysosome function. We found progranulin deficiency in neurons increased autophagy and caused abnormally enlarged lysosomes and boosting progranulin levels restored autophagy and lysosome size to control levels. Our data link the ALP to neuronal progranulin: progranulin levels are regulated by autophagy and, in turn, progranulin regulates the ALP. Restoring progranulin levels by targeting genetic modifiers reversed FTLD functional deficits, opening up potential opportunities for future therapeutics development.
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