ArticleNature neuroscience2013
Neuroprotection and lifespan extension in Ppt1(-/-) mice by NtBuHA: therapeutic implications for INCL.
Article in Nature neuroscience, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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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
47 citing papers in PubMed, 78 citations in OpenAlex.
- Oral cysteamine bitartrate and N-acetylcysteine for patients with infantile neuronal ceroid lipofuscinosis: a pilot study.The Lancet. Neurology · 2014Trial
- Neuronal ceroid lipofuscinosis: underlying mechanisms and emerging therapeutic targets.Nature reviews. Neurology · 2025Review
- AAV-delivered PPT1 provides long-term neurological benefits in CLN1 mice and achieves therapeutic levels in sheep brain.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Niemann Pick C1 mistargeting disrupts lysosomal cholesterol homeostasis contributing to neurodegeneration in a Batten disease model.Science advances · 2025Article
- Review
- Neuronal Ceroid Lipofuscinosis-Concepts, Classification, and Avenues for Therapy.CNS neuroscience & therapeutics · 2025Review
- Synthetic and semi-synthetic antioxidants in medicine and food industry: a review.Frontiers in pharmacology · 2025Review
- Protein regulatory network mediated by palmitoylation modifications in the pathological progression of Parkinson's disease: a narrative review.Frontiers in immunology · 2025Review
- GABATranslational psychiatry · 2024Article
- Altered Protein Palmitoylation as Disease Mechanism in Neurodegenerative Disorders.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Review
- Lucanthone, a Potential PPT1 Inhibitor, Perturbs Stemness, Reduces Tumor Microtube Formation, and Slows the Growth of Temozolomide-Resistant Gliomas In Vivo.The Journal of pharmacology and experimental therapeutics · 2024Article
- Loss of Depalmitoylation Disrupts Homeostatic Plasticity of AMPARs in a Mouse Model of Infantile Neuronal Ceroid Lipofuscinosis.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2023Article
- An innovative hematopoietic stem cell gene therapy approach benefits CLN1 disease in the mouse model.EMBO molecular medicine · 2023Article
- S-Palmitoylation of Synaptic Proteins in Neuronal Plasticity in Normal and Pathological Brains.Cells · 2023Review
- Lost in traffic: consequences of altered palmitoylation in neurodegeneration.Frontiers in physiology · 2023Review
- Seizures in PPT1 Knock-In Mice Are Associated with Inflammatory Activation of Microglia.International journal of molecular sciences · 2022Article
- APT1-Mediated Depalmitoylation Regulates Hippocampal Synaptic Plasticity.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2022Article
- GFAP hyperpalmitoylation exacerbates astrogliosis and neurodegenerative pathology in PPT1-deficient mice.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Human INCL fibroblasts display abnormal mitochondrial and lysosomal networks and heightened susceptibility to ROS-induced cell death.PloS one · 2021Article
- Gauging the role and impact of drug interactions and repurposing in neurodegenerative disorders.Current research in pharmacology and drug discovery · 2021Review
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating childhood neurodegenerative lysosomal storage disease (LSD) that has no effective treatment. It is caused by inactivating mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. PPT1 deficiency impairs the cleavage of thioester linkage in palmitoylated proteins (constituents of ceroid), preventing degradation by lysosomal hydrolases. Consequently, accumulation of lysosomal ceroid leads to INCL. Thioester linkage is cleaved by nucleophilic attack. Hydroxylamine, a potent nucleophilic cellular metabolite, may have therapeutic potential for INCL, but its toxicity precludes clinical application. We found that a hydroxylamine derivative, N-(tert-Butyl) hydroxylamine (NtBuHA), was non-toxic, cleaved thioester linkage in palmitoylated proteins and mediated lysosomal ceroid depletion in cultured cells from INCL patients. In Ppt1(-/-) mice, which mimic INCL, NtBuHA crossed the blood-brain barrier, depleted lysosomal ceroid, suppressed neuronal apoptosis, slowed neurological deterioration and extended lifespan. Our findings provide a proof of concept that thioesterase-mimetic and antioxidant small molecules such as NtBuHA are potential drug targets for thioesterase deficiency diseases such as INCL.
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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.