ArticleHuman molecular genetics2017
Progranulin-mediated deficiency of cathepsin D results in FTD and NCL-like phenotypes in neurons derived from FTD patients.
Article in Human molecular genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 89 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
89 citing papers in PubMed, 142 citations in OpenAlex.
- Progranulin AAV gene therapy for frontotemporal dementia: translational studies and phase 1/2 trial interim results.Nature medicine · 2024Trial
- Lysosomal dysfunction in neurodegenerative disease.Nature reviews. Neurology · 2026Review
- Human TDP-43 expression worsens FTD-related phenotypes in progranulin-insufficient mice.Neurobiology of disease · 2026Article
- Hippocampal neuronal progranulin mediates estrogen‑deficiency‑induced affective vulnerability and lysosomal-autophagic dysfunction.Molecular psychiatry · 2026Article
- Granulin loss and TMEM106B risk converge on lysosomal C-terminal fragment pathology in frontotemporal dementia.bioRxiv : the preprint server for biology · 2026Article
- PARK19 truncation mutant Dnajc6 causes lysosomal deficiency-induced upregulation of pathologic α-synuclein and neurodegeneration of substantia nigra dopaminergic cells in PARK19 knockin mice.NPJ Parkinson's disease · 2026Article
- Mitochondria and Lipid Defects in Hereditary Progranulin-Related Frontotemporal Dementia.Cells · 2026Article
- Progranulin promotes glioma progression via interaction with cathepsin D and serves as a diagnostic and prognostic biomarker.Discover oncology · 2026Article
- Patient-derived induced pluripotent stem cells with a C9orf72 expansion as a model to study frontotemporal dementia pathologies.Molecular biology of the cell · 2025Article
- Generation of Induced Pluripotent Stem Cells and Neuroepithelial Stem Cells from a Family with the Pathogenic Variant p.Q337X in Progranulin.International journal of molecular sciences · 2025Article
- Delivering Progranulin to Astrocytic Lysosomes Promotes Growth of Co-Cultured Neurons.Journal of neurochemistry · 2025Article
- Targeting Granulin Haploinsufficiency in Frontotemporal Dementia: From Genetic Mechanisms to Therapeutics.International journal of molecular sciences · 2025Review
- Reduction of sphingomyelinase activity associated with progranulin deficiency and frontotemporal dementia.Neurobiology of disease · 2025Article
- The role of endolysosomal progranulin and TMEM106B in neurodegenerative diseases.Molecular neurodegeneration · 2025Review
- TFEB overexpression alleviates autophagy-lysosomal deficits caused by progranulin insufficiency.Scientific reports · 2025Article
- PGRN as an emerging regulator of lipid metabolism in neurodegenerative diseases.Communications biology · 2025Review
- Progranulin deficiency in the brain: the interplay between neuronal and non-neuronal cells.Translational neurodegeneration · 2025Review
- Microglial progranulin differently regulates hypothalamic lysosomal function in lean and obese conditions via cleavage-dependent mechanisms.Journal of neuroinflammation · 2025Article
- Molecular mechanisms and targeted therapy of progranulin in metabolic diseases.Frontiers in endocrinology · 2025Review
- The role of autophagy in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).Autophagy reports · 2025Review
29 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Frontotemporal dementia (FTD) encompasses a group of neurodegenerative disorders characterized by cognitive and behavioral impairments. Heterozygous mutations in progranulin (PGRN) cause familial FTD and result in decreased PGRN expression, while homozygous mutations result in complete loss of PGRN expression and lead to the neurodegenerative lysosomal storage disorder neuronal ceroid lipofuscinosis (NCL). However, how dose-dependent PGRN mutations contribute to these two different diseases is not well understood. Using iPSC-derived human cortical neurons from FTD patients harboring PGRN mutations, we demonstrate that PGRN mutant neurons exhibit decreased nuclear TDP-43 and increased insoluble TDP-43, as well as enlarged electron-dense vesicles, lipofuscin accumulation, fingerprint-like profiles and granular osmiophilic deposits, suggesting that both FTD and NCL-like pathology are present in PGRN patient neurons as compared to isogenic controls. PGRN mutant neurons also show impaired lysosomal proteolysis and decreased activity of the lysosomal enzyme cathepsin D. Furthermore, we find that PGRN interacts with cathepsin D, and that PGRN increases the activity of cathepsin D but not cathepsins B or L. Finally, we show that granulin E, a cleavage product of PGRN, is sufficient to increase cathepsin D activity. This functional relationship between PGRN and cathepsin D provides a possible explanation for overlapping NCL-like pathology observed in patients with mutations in PGRN or CTSD, the gene encoding cathepsin D. Together, our work identifies PGRN as an activator of lysosomal cathepsin D activity, and suggests that decreased cathepsin D activity due to loss of PGRN contributes to both FTD and NCL pathology in a dose-dependent manner.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.