{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:54:19Z","timestamp":1787187259355,"version":"build-2736575974"},"reference-count":65,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2024,11,12]],"date-time":"2024-11-12T00:00:00Z","timestamp":1731369600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["RGPIN-2020-07215"],"award-info":[{"award-number":["RGPIN-2020-07215"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,1,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Sandhoff disease (SD), a fatal and rare lysosomal storage disorder (LSD), is caused by a deficiency of the enzyme \u03b2-hexosaminidase B and leads to severe accumulation of GM2 gangliosides in lysosomes, primarily within the central nervous system (CNS). This accumulation results in severe neurological impairment, lower motor neuron disease, and death. Currently, there are no effective therapies available for SD. Here, we explored the role of endoplasmic reticulum (ER) stress in the spinal cord during disease progression in an established mouse model of SD and revealed the beneficial outcome of off-label treatment with the FDA-approved drug, 4-phenylbutyric acid (4-PBA). We analyzed the expression and localization of ER stress and cellular apoptosis markers, which revealed significant upregulation of these factors within motor neurons. Additionally, we observed a\u2009&amp;gt;\u200950% reduction in neuronal numbers throughout all spinal cord regions. Our studies also tested the impact of the chemical chaperone 4-PBA on ER stress in mice, and following administration, we observed significant improvements in motor neuromuscular function and life span throughout disease progression. 4-PBA treatment significantly reduced apoptosis in spinal cord neurons and increased the number of choline acetyltransferase (ChAT)-positive neurons, with little effect on astrogliosis or sensory interneurons. Overall, this study provides strong evidence for the role of chronic ER stress in the pathophysiology of SD and highlights 4-PBA as a promising therapeutic treatment for SD and potentially other related LSDs.<\/jats:p>","DOI":"10.1093\/hmg\/ddae153","type":"journal-article","created":{"date-parts":[[2024,11,12]],"date-time":"2024-11-12T09:35:46Z","timestamp":1731404146000},"page":"32-46","source":"Crossref","is-referenced-by-count":9,"title":["4-Phenylbutyric acid mitigates ER stress-induced neurodegeneration in the spinal cords of a GM2 gangliosidosis mouse model"],"prefix":"10.1093","volume":"34","author":[{"given":"Fiona E","family":"Weaver","sequence":"first","affiliation":[{"name":"Department of Biology, McMaster University , 1280 Main St. W., Hamilton, ON L8S 4K1,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"White","sequence":"additional","affiliation":[{"name":"Department of Biology, McMaster University , 1280 Main St. W., Hamilton, ON L8S 4K1,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allyson M","family":"Peek","sequence":"additional","affiliation":[{"name":"Department of Biology, McMaster University , 1280 Main St. W., Hamilton, ON L8S 4K1,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin A","family":"Nurse","sequence":"additional","affiliation":[{"name":"Department of Biology, McMaster University , 1280 Main St. W., Hamilton, ON L8S 4K1,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard C","family":"Austin","sequence":"additional","affiliation":[{"name":"Department of Medicine , Division of Nephrology, , 1280 Main Street W., Hamilton, ON, L8S 4L8,","place":["Canada"]},{"name":"McMaster University , Division of Nephrology, , 1280 Main Street W., Hamilton, ON, L8S 4L8,","place":["Canada"]},{"name":"The Research Institute of St. Joe\u2019s Hamilton and The Hamilton Center for Kidney Research , 50 Charlton Avenue E., Hamilton, ON, L8N 4A6,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8780-4981","authenticated-orcid":false,"given":"Suleiman A","family":"Igdoura","sequence":"additional","affiliation":[{"name":"Department of Biology, McMaster University , 1280 Main St. W., Hamilton, ON L8S 4K1,","place":["Canada"]},{"name":"Department of Pathology and Molecular Medicine, McMaster University , 1200 Main Street W., Hamilton, ON, L8S 4K1,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,11,12]]},"reference":[{"key":"2025012315421849100_ref1","doi-asserted-by":"crossref","first-page":"6213","DOI":"10.3390\/ijms21176213","article-title":"GM2 Gangliosidoses: clinical features, pathophysiological aspects, and current therapies","volume":"21","author":"Leal","year":"2020","journal-title":"Int J Mol 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Degener"},{"key":"2025012315421849100_ref5","doi-asserted-by":"crossref","first-page":"2963","DOI":"10.1212\/WNL.96.15_supplement.2963","article-title":"Spinal muscular atrophy mimicking adult-onset GM2 Gangliosidosis AB variant: a case report (2963)","volume":"96","author":"Klopman","year":"2021","journal-title":"Neurology"},{"key":"2025012315421849100_ref6","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/j.gene.2013.06.030","article-title":"Late onset GM2 gangliosidosis mimicking spinal muscular atrophy","volume":"527","author":"Jamrozik","year":"2013","journal-title":"Gene"},{"key":"2025012315421849100_ref7","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1136\/jnnp.2009.177089","article-title":"New cases of adult-onset Sandhoff disease with a cerebellar or lower motor neuron phenotype","volume":"81","author":"Delnooz","year":"2010","journal-title":"J Neurol Neurosurg 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