ArticlePLoS genetics2019
Age- and stress-associated C. elegans granulins impair lysosomal function and induce a compensatory HLH-30/TFEB transcriptional response.
Article in PLoS genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 44 citations in OpenAlex.
- Monospecific antibodies reveal reduction of granulins in frontotemporal dementia caused byMolecular neurodegeneration advances · 2026Article
- The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases.Progress in neurobiology · 2025Review
- Development of AL101 (GSK4527226), a progranulin-elevating monoclonal antibody, as a potential treatment for Alzheimer's disease.Alzheimer's research & therapy · 2025Article
- PGRN as an emerging regulator of lipid metabolism in neurodegenerative diseases.Communications biology · 2025Review
- Granulins rescue inflammation, lysosome dysfunction, lipofuscin, and neuropathology in a mouse model of progranulin deficiency.Cell reports · 2024Article
- Benzoxazole-derivatives enhance progranulin expression and reverse the aberrant lysosomal proteome caused by GRN haploinsufficiency.Nature communications · 2024Article
- The progranulin cleavage product granulin 3 exerts a dominant negative effect on animal fitness.Human molecular genetics · 2024Article
- Review
- Targeting Progranulin as an Immuno-Neurology Therapeutic Approach.International journal of molecular sciences · 2023Review
- Novel Insight into Functions of Transcription Factor EB (TFEB) in Alzheimer's Disease and Parkinson's Disease.Aging and disease · 2023Review
- Mutations in α-synuclein, TDP-43 and tau prolong protein half-life through diminished degradation by lysosomal proteases.Molecular neurodegeneration · 2023Article
- Article
- Simple models to understand complex disease: 10 years of progress fromFrontiers in neuroscience · 2023Review
- Microglia regulate brain progranulin levels through the endocytosis/lysosomal pathway.JCI insight · 2021Article
- Processing of progranulin into granulins involves multiple lysosomal proteases and is affected in frontotemporal lobar degeneration.Molecular neurodegeneration · 2021Article
- Lysosome dysfunction as a cause of neurodegenerative diseases: Lessons from frontotemporal dementia and amyotrophic lateral sclerosis.Neurobiology of disease · 2021Review
- Review
- Review
- Progranulin Adsorbs to Polypropylene Tubes and Disrupts Functional Assays: Implications for Research, Biomarker Studies, and Therapeutics.Frontiers in neuroscience · 2020Article
- MiT/TFE Family of Transcription Factors: An Evolutionary Perspective.Frontiers in cell and developmental biology · 2020Review
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
The progressive failure of protein homeostasis is a hallmark of aging and a common feature in neurodegenerative disease. As the enzymes executing the final stages of autophagy, lysosomal proteases are key contributors to the maintenance of protein homeostasis with age. We previously reported that expression of granulin peptides, the cleavage products of the neurodegenerative disease protein progranulin, enhance the accumulation and toxicity of TAR DNA binding protein 43 (TDP-43) in Caenorhabditis elegans (C. elegans). In this study we show that C. elegans granulins are produced in an age- and stress-dependent manner. Granulins localize to the endolysosomal compartment where they impair lysosomal protease expression and activity. Consequently, protein homeostasis is disrupted, promoting the nuclear translocation of the lysosomal transcription factor HLH-30/TFEB, and prompting cells to activate a compensatory transcriptional program. The three C. elegans granulin peptides exhibited distinct but overlapping functional effects in our assays, which may be due to amino acid composition that results in distinct electrostatic and hydrophobicity profiles. Our results support a model in which granulin production modulates a critical transition between the normal, physiological regulation of protease activity and the impairment of lysosomal function that can occur with age and disease.
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