ArticleHuman molecular genetics2016
Genetic and pharmacological evidence implicates cathepsins in Niemann-Pick C cerebellar degeneration.
Article in Human molecular genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 36 citations in OpenAlex.
- Lack of cathepsin B increases severity in Niemann-Pick disease, type C1 mice.Neuroscience letters · 2026Article
- Mito-TEMPO improves survival rates inScience advances · 2026Article
- Identification of serum protein biomarkers in individuals with Niemann-Pick disease, type C1.Biomarker research · 2026Article
- Cystatin B Attenuates Cerebral Ischemia Reperfusion Injury by Inhibiting the JAK2/STAT3 Signaling Pathway.CNS neuroscience & therapeutics · 2026Article
- Identification of serum protein biomarkers in individuals with Niemann-Pick disease, type C1.Research square · 2026Article
- Identification of serum protein biomarkers in individuals with Niemann-Pick disease, type C1.medRxiv : the preprint server for health sciences · 2026Article
- Prosaposin Is Cleaved Into Saposins by Multiple Cathepsins in a Progranulin-Regulated Fashion.Journal of neurochemistry · 2026Article
- Review
- NPC1 links cholesterol trafficking to microglial morphology via the gastrosome.Nature communications · 2024Article
- Mutant induced neurons and humanized mice enable identification of Niemann-Pick type C1 proteostatic therapies.JCI insight · 2024Article
- Species-specific differences in NPC1 protein trafficking govern therapeutic response in Niemann-Pick type C disease.JCI insight · 2022Article
- TDP-43 proteinopathy occurs independently of autophagic substrate accumulation and underlies nuclear defects in Niemann-Pick C disease.Neuropathology and applied neurobiology · 2021Article
- Selective Neutral pH Inhibitor of Cathepsin B Designed Based on Cleavage Preferences at Cytosolic and Lysosomal pH Conditions.ACS chemical biology · 2021Article
- NPC1-mTORC1 Signaling Couples Cholesterol Sensing to Organelle Homeostasis and Is a Targetable Pathway in Niemann-Pick Type C.Developmental cell · 2021Article
- Alterations in Lysosome Homeostasis in Lipid-Related Disorders: Impact on Metabolic Tissues and Immune Cells.Frontiers in cell and developmental biology · 2021Review
- Cathepsins in neuronal plasticity.Neural regeneration research · 2021Article
- Oxidative Stress and Alterations in the Antioxidative Defense System in Neuronal Cells Derived from NPC1 Patient-Specific Induced Pluripotent Stem Cells.International journal of molecular sciences · 2020Article
- Fbxo2 mediates clearance of damaged lysosomes and modifies neurodegeneration in the Niemann-Pick C brain.JCI insight · 2020Article
- Single Cell Transcriptome Analysis of Niemann-Pick Disease, Type C1 Cerebella.International journal of molecular sciences · 2020Article
- Penetrating Traumatic Brain Injury Triggers Dysregulation of Cathepsin B Protein Levels Independent of Cysteine Protease Activity in Brain and Cerebral Spinal Fluid.Journal of neurotrauma · 2020Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Niemann-Pick C1 (NPC) disease, an autosomal recessive lipid trafficking disorder caused by loss-of-function mutations in the NPC1 gene, is characterized by progressive neurodegeneration resulting in cognitive impairment, ataxia and early death. Little is known about the cellular pathways leading to neuron loss. Here, we studied the effects of diminishing expression of cystatin B, an endogenous inhibitor of cathepsins B, H and L, on the development of NPC neuropathology. We show that decreased expression of cystatin B in patient fibroblasts enhances cathepsin activity. Deletion of the encoding Cstb gene in Npc1-deficient mice resulted in striking deleterious effects, particularly within the cerebellum where diffuse loss of Purkinje cells was observed in young mice. This severe pathology occurred through cell autonomous mechanisms that triggered Purkinje cell death. Moreover, our analyses demonstrated the mislocalization of lysosomal cathepsins within the cytosol of Npc1-deficient Purkinje cells. We provide evidence that this may be a consequence of damage to lysosomal membranes by reactive oxygen species (ROS), leading to the leakage of lysosomal contents that culminates in apoptotic cell death. Consistent with this notion, toxicity from ROS was attenuated in an NPC cell model by cystatin B over-expression or pharmacological inhibition of cathepsin B. The observation that Npc1 and Cstb deletion genetically interact to potently enhance the degenerative phenotype of the NPC cerebellum provides strong support for the notion that lysosomal membrane permeabilization contributes to cerebellar degeneration in NPC disease.
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