{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T05:05:42Z","timestamp":1793423142101,"version":"4.5.0"},"reference-count":57,"publisher":"American Society for Cell Biology (ASCB)","issue":"24","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["MBoC"],"published-print":{"date-parts":[[2016,12]]},"abstract":"<jats:p>Loss of function of the enzyme \u03b2-hexosaminidase A (HexA) causes the lysosomal storage disorder Tay\u2013Sachs disease (TSD). It has been proposed that mutations in the \u03b1 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 \u03b1 mutants, seeking to identify relevant cellular quality control mechanisms. The \u03b1 mutants E482K and G269S are defective in enzymatic activity, unprocessed by lysosomal proteases, and exhibit altered folding pathways compared with wild-type \u03b1. E482K is more severely misfolded than G269S, as observed by its aggregation and inability to associate with the HexA \u03b2 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 \u03b1 degradation. Additionally, growth of patient fibroblasts at a permissive temperature or with chemical chaperones increases cellular Hex activity by improving mutant \u03b1 folding. Therefore modulation of the ER quality control systems may be a potential therapeutic route for improving some forms of TSD.<\/jats:p>","DOI":"10.1091\/mbc.e16-01-0012","type":"journal-article","created":{"date-parts":[[2016,9,29]],"date-time":"2016-09-29T03:19:15Z","timestamp":1475119155000},"page":"3813-3827","source":"Crossref","is-referenced-by-count":55,"title":["Tay\u2013Sachs disease mutations in HEXA target the \u03b1 chain of hexosaminidase A to endoplasmic reticulum\u2013associated degradation"],"prefix":"10.1091","volume":"27","author":[{"given":"Devin","family":"Dersh","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Children\u2019s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichiro","family":"Iwamoto","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Children\u2019s Hospital of 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