ArticleMolecular biology of the cell2016
Tay-Sachs disease mutations in HEXA target the α chain of hexosaminidase A to endoplasmic reticulum-associated degradation.
Article in Molecular biology of the cell, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed.
- Modeling Tay-Sachs Disease in Astrocyte-like Cells Reveals Significant Changes in the Transcriptomic Profile.International journal of molecular sciences · 2026Article
- Impairment of Macrophage Functions by the Senescence-Associated Secretory Phenotype of Vascular Smooth Muscle Cells-Brief Report.Arteriosclerosis, thrombosis, and vascular biology · 2026Article
- Comparative Analysis of Proteoform Clean-Up Methods for In-Depth Top-Down Proteomics.Proteomics · 2025Article
- Microglial replacement in a Sandhoff disease mouse model reveals myeloid-derived β-hexosaminidase is necessary for neuronal health.Nature communications · 2025Article
- Precise template-free correction restores gene function in Tay-Sachs disease while reframing is ineffective.Molecular therapy. Nucleic acids · 2025Article
- GRASP55 regulates sorting and maturation of the lysosomal enzyme β-hexosaminidase A.Molecular biology of the cell · 2025Article
- Simultaneous surgery for gastrostomy and laryngotracheal separation in a patient with Tay‒Sachs disease.Human genome variation · 2024Article
- Myeloid-derived β-hexosaminidase is essential for neuronal health and lysosome function: implications for Sandhoff disease.bioRxiv : the preprint server for biology · 2024Article
- Emerging Perspectives on Prime Editor Delivery to the Brain.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Mutations in Glycosyltransferases and Glycosidases: Implications for Associated Diseases.Biomolecules · 2024Article
- Decoding Neurodegeneration: A Comprehensive Review of Molecular Mechanisms, Genetic Influences, and Therapeutic Innovations.International journal of molecular sciences · 2023Review
- Mysterious sphingolipids: metabolic interrelationships at the center of pathophysiology.Frontiers in physiology · 2023Review
- spJournal of enzyme inhibition and medicinal chemistry · 2022Article
- CRISPR/nCas9-Based Genome Editing on GM2 Gangliosidoses Fibroblasts via Non-Viral Vectors.International journal of molecular sciences · 2022Article
- Loss of Function of Mutant IDS Due to Endoplasmic Reticulum-Associated Degradation: New Therapeutic Opportunities for Mucopolysaccharidosis Type II.International journal of molecular sciences · 2021Review
- Article
- Serum Cytokine Profile, Beta-Hexosaminidase A Enzymatic Activity and GMLife (Basel, Switzerland) · 2021Article
- Novel HEXA variants in Korean children with Tay-Sachs disease with regression of neurodevelopment from infancy.Molecular genetics & genomic medicine · 2021Article
- Regulation of autophagy by inhibitory CSPG interactions with receptor PTPσ and its impact on plasticity and regeneration after spinal cord injury.Experimental neurology · 2020Review
- Review
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3 authors.
Funding
Abstract
Loss of function of the enzyme β-hexosaminidase A (HexA) causes the lysosomal storage disorder Tay-Sachs disease (TSD). It has been proposed that mutations in the α chain of HexA can impair folding, enzyme assembly, and/or trafficking, yet there is surprisingly little known about the mechanisms of these potential routes of pathogenesis. We therefore investigated the biosynthesis and trafficking of TSD-associated HexA α mutants, seeking to identify relevant cellular quality control mechanisms. The α mutants E482K and G269S are defective in enzymatic activity, unprocessed by lysosomal proteases, and exhibit altered folding pathways compared with wild-type α. E482K is more severely misfolded than G269S, as observed by its aggregation and inability to associate with the HexA β chain. Importantly, both mutants are retrotranslocated from the endoplasmic reticulum (ER) to the cytosol and are degraded by the proteasome, indicating that they are cleared via ER-associated degradation (ERAD). Leveraging these discoveries, we observed that manipulating the cellular folding environment or ERAD pathways can alter the kinetics of mutant α degradation. Additionally, growth of patient fibroblasts at a permissive temperature or with chemical chaperones increases cellular Hex activity by improving mutant α folding. Therefore modulation of the ER quality control systems may be a potential therapeutic route for improving some forms of TSD.
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