ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2013
Lysosomal membrane permeability stimulates protein aggregate formation in neurons of a lysosomal disease.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 54 citations in OpenAlex.
- Restoration of lysosomal membrane integrity in cell models of Pompe disease depends on fatty acid synthase and its product palmitic acid.Cellular & molecular biology letters · 2026Article
- The NLRP6 inflammasome is activated by sterile or pathogen-induced endolysosomal damage.The EMBO journal · 2026Article
- Recreating pathophysiology of CLN2 disease and demonstrating reversion by TPP1 gene therapy in hiPSC-derived retinal organoids and retina-on-chip.Cell reports. Medicine · 2025Article
- Advances in Fluorescence Techniques for the Detection of Hydroxyl Radicals near DNA and Within Organelles and Membranes.Antioxidants (Basel, Switzerland) · 2025Review
- Extracellular Vesicles as Tools for Crossing the Blood-Brain Barrier to Treat Lysosomal Storage Diseases.Life (Basel, Switzerland) · 2025Review
- Deficiency of galactosyl-ceramidase in adult oligodendrocytes worsens disease severity during chronic experimental allergic encephalomyelitis.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Molecular Mechanisms in Pathophysiology of Mucopolysaccharidosis and Prospects for Innovative Therapy.International journal of molecular sciences · 2024Review
- Review
- Fbxo2 mediates clearance of damaged lysosomes and modifies neurodegeneration in the Niemann-Pick C brain.JCI insight · 2020Article
- Metabolism of Glycosphingolipids and Their Role in the Pathophysiology of Lysosomal Storage Disorders.International journal of molecular sciences · 2020Review
- Article
- Nanoparticle-Mediated Therapeutic Application for Modulation of Lysosomal Ion Channels and Functions.Pharmaceutics · 2020Review
- Mice deficient in the lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1) display a complex retinal phenotype.Scientific reports · 2019Article
- Current concepts in the neuropathogenesis of mucolipidosis type IV.Journal of neurochemistry · 2019Review
- Autophagy-lysosome pathway alterations and alpha-synuclein up-regulation in the subtype of neuronal ceroid lipofuscinosis, CLN5 disease.Scientific reports · 2019Article
- Hypoxia-ischemia alters distribution of lysosomal proteins in rat cortex and hippocampus.Biology open · 2018Article
- Loss of CLN7 results in depletion of soluble lysosomal proteins and impaired mTOR reactivation.Human molecular genetics · 2018Article
- Genetics and Therapies for GM2 Gangliosidosis.Current gene therapy · 2018Review
- A tripeptidyl peptidase 1 is a binding partner of the Golgi pH regulator (GPHR) inDisease models & mechanisms · 2017Article
- Acid Ceramidase Deficiency in Mice Results in a Broad Range of Central Nervous System Abnormalities.The American journal of pathology · 2017Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Protein aggregates are a common pathological feature of neurodegenerative diseases and several lysosomal diseases, but it is currently unclear what aggregates represent for pathogenesis. Here we report the accumulation of intraneuronal aggregates containing the macroautophagy adapter proteins p62 and NBR1 in the neurodegenerative lysosomal disease late-infantile neuronal ceroid lipofuscinosis (CLN2 disease). CLN2 disease is caused by a deficiency in the lysosomal enzyme tripeptidyl peptidase I, which results in aberrant lysosomal storage of catabolites, including the subunit c of mitochondrial ATP synthase (SCMAS). In an effort to define the role of aggregates in CLN2, we evaluated p62 and NBR1 accumulation in the CNS of Cln2(-/-) mice. Although increases in p62 and NBR1 often suggest compromised degradative mechanisms, we found normal ubiquitin-proteasome system function and only modest inefficiency in macroautophagy late in disease. Importantly, we identified that SCMAS colocalizes with p62 in extra-lysosomal aggregates in Cln2(-/-) neurons in vivo. This finding is consistent with SCMAS being released from lysosomes, an event known as lysosomal membrane permeability (LMP). We predicted that LMP and storage release from lysosomes results in the sequestration of this material as cytosolic aggregates by p62 and NBR1. Notably, LMP induction in primary neuronal cultures generates p62-positive aggregates and promotes p62 localization to lysosomal membranes, supporting our in vivo findings. We conclude that LMP is a previously unrecognized pathogenic event in CLN2 disease that stimulates cytosolic aggregate formation. Furthermore, we offer a novel role for p62 in response to LMP that may be relevant for other diseases exhibiting p62 accumulation.
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