ArticleThe Journal of biological chemistry2015
Unbiased Cell-based Screening in a Neuronal Cell Model of Batten Disease Highlights an Interaction between Ca2+ Homeostasis, Autophagy, and CLN3 Protein Function.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers, 2 of them syntheses that pooled it.
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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.
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Who cites it
49 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)Autophagy · 2021Guideline
- Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).Autophagy · 2016Guideline
- Elevated tripeptidyl-peptidase 1 corrects multiple disease phenotypes in a mouse model of juvenile neuronal ceroid lipofuscinosis.Molecular therapy. Methods & clinical development · 2025Article
- Discovery of Functionalized 1Journal of medicinal chemistry · 2025Article
- Expanded Phenotype of theCells · 2025Article
- Loss of CLN3 in microglia leads to impaired lipid metabolism and myelin turnover.Communications biology · 2024Article
- Loss of the batten disease protein CLN3 leads to mis-trafficking of M6PR and defective autophagic-lysosomal reformation.Nature communications · 2023Article
- Converging links between adult-onset neurodegenerative Alzheimer's disease and early life neurodegenerative neuronal ceroid lipofuscinosis?Neural regeneration research · 2023Review
- TPC2 rescues lysosomal storage in mucolipidosis type IV, Niemann-Pick type C1, and Batten disease.EMBO molecular medicine · 2022Article
- Article
- Asthma Susceptibility GeneAmerican journal of respiratory cell and molecular biology · 2022Article
- Review
- Glial Dysfunction and Its Contribution to the Pathogenesis of the Neuronal Ceroid Lipofuscinoses.Frontiers in neurology · 2022Review
- Autophagy in the Neuronal Ceroid Lipofuscinoses (Batten Disease).Frontiers in cell and developmental biology · 2022Review
- Patient-Derived Induced Pluripotent Stem Cell Models for Phenotypic Screening in the Neuronal Ceroid Lipofuscinoses.Molecules (Basel, Switzerland) · 2021Review
- CLN3, at the crossroads of endocytic trafficking.Neuroscience letters · 2021Article
- The Role of iPSC Modeling Toward Projection of Autophagy Pathway in Disease Pathogenesis: Leader or Follower.Stem cell reviews and reports · 2021Review
- Therapeutics Development for Alagille Syndrome.Frontiers in pharmacology · 2021Review
- Stem Cell Applications in Lysosomal Storage Disorders: Progress and Ongoing Challenges.Advances in experimental medicine and biology · 2021Article
- An iPSC-Derived Neuron Model of CLN3 Disease Facilitates Small Molecule Phenotypic Screening.ACS pharmacology & translational science · 2020Article
Corrections and comments
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Authors and funding
13 authors.
Funding
Abstract
Abnormal accumulation of undigested macromolecules, often disease-specific, is a major feature of lysosomal and neurodegenerative disease and is frequently attributed to defective autophagy. The mechanistic underpinnings of the autophagy defects are the subject of intense research, which is aided by genetic disease models. To gain an improved understanding of the pathways regulating defective autophagy specifically in juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease), a neurodegenerative disease of childhood, we developed and piloted a GFP-microtubule-associated protein 1 light chain 3 (GFP-LC3) screening assay to identify, in an unbiased fashion, genotype-sensitive small molecule autophagy modifiers, employing a JNCL neuronal cell model bearing the most common disease mutation in CLN3. Thapsigargin, a sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) Ca(2+) pump inhibitor, reproducibly displayed significantly more activity in the mouse JNCL cells, an effect that was also observed in human-induced pluripotent stem cell-derived JNCL neural progenitor cells. The mechanism of thapsigargin sensitivity was Ca(2+)-mediated, and autophagosome accumulation in JNCL cells could be reversed by Ca(2+) chelation. Interrogation of intracellular Ca(2+) handling highlighted alterations in endoplasmic reticulum, mitochondrial, and lysosomal Ca(2+) pools and in store-operated Ca(2+) uptake in JNCL cells. These results further support an important role for the CLN3 protein in intracellular Ca(2+) handling and in autophagic pathway flux and establish a powerful new platform for therapeutic screening.
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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.