{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T18:48:11Z","timestamp":1789152491197,"version":"build-2803163510"},"reference-count":60,"publisher":"MDPI AG","issue":"22","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":[{"name":"National Science and Technology Council","award":["NSTC-109-2314-B-195-015-MY3"],"award-info":[{"award-number":["NSTC-109-2314-B-195-015-MY3"]}]},{"name":"National Science and Technology Council","award":["NSTC-112-2320-B-195-001"],"award-info":[{"award-number":["NSTC-112-2320-B-195-001"]}]},{"name":"National Science and Technology Council","award":["MMH-E-111-02"],"award-info":[{"award-number":["MMH-E-111-02"]}]},{"name":"National Science and Technology Council","award":["MMH-E-112-02"],"award-info":[{"award-number":["MMH-E-112-02"]}]},{"name":"MacKay Memorial Hospital","award":["NSTC-109-2314-B-195-015-MY3"],"award-info":[{"award-number":["NSTC-109-2314-B-195-015-MY3"]}]},{"name":"MacKay Memorial Hospital","award":["NSTC-112-2320-B-195-001"],"award-info":[{"award-number":["NSTC-112-2320-B-195-001"]}]},{"name":"MacKay Memorial Hospital","award":["MMH-E-111-02"],"award-info":[{"award-number":["MMH-E-111-02"]}]},{"name":"MacKay Memorial Hospital","award":["MMH-E-112-02"],"award-info":[{"award-number":["MMH-E-112-02"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Leukodystrophies represent a heterogeneous group of disorders characterized by specific genetic mutations, metabolic abnormalities, and degeneration of white matter in the central nervous system. These disorders are classified into several categories, with X-linked adrenoleukodystrophy (X-ALD), metachromatic leukodystrophy (MLD), and globoid cell leukodystrophy (GLD) being the most prevalent demyelinating leukodystrophies in pediatric populations. Maintaining proteostasis, which is critical for normal cellular function, relies fundamentally on the ubiquitin\u2013proteasome system (UPS) and autophagy for the degradation of misfolded and damaged proteins. Compelling evidence has highlighted the critical roles of UPS and autophagy dysfunction in the pathogenesis of neurodegenerative diseases. Given the complex and poorly understood pathomechanisms underlying demyelinating leukodystrophies, coupled with the pressing need for effective therapeutic strategies, this review aims to systemically analyze the molecular and pathological evidence linking UPS and autophagy dysfunction to demyelinating leukodystrophies, specifically X-ALD and GLD. Furthermore, we will assess the therapeutic potential of autophagy modulators in the management of X-ALD and GLD, with the objective to inspire further research into therapeutic approaches that target autophagy and UPS pathways. Novel therapies that enhance autophagy and UPS function hold promise as complementary regimens in combination therapies aimed at achieving comprehensive correction of the pathogenic mechanisms in demyelinating leukodystrophies.<\/jats:p>","DOI":"10.3390\/cells13221873","type":"journal-article","created":{"date-parts":[[2024,11,12]],"date-time":"2024-11-12T08:12:39Z","timestamp":1731399159000},"page":"1873","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Emerging Role of Ubiquitin Proteasome System and Autophagy in Pediatric Demyelinating Leukodystrophies and Therapeutic Opportunity"],"prefix":"10.3390","volume":"13","author":[{"given":"Dar-Shong","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Translational Medicine, MacKay Memorial Hospital, 92, Section 2, Chung-Shan North Road, Taipei 10449, Taiwan"},{"name":"Department of Pediatrics, MacKay Memorial Hospital, Taipei 10449, Taiwan"},{"name":"Department of Medicine, MacKay Medical College, New Taipei 25245, Taiwan"},{"name":"Department of Medical Research, MacKay Memorial Hospital, Taipei 10449, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7942-5823","authenticated-orcid":false,"given":"Che-Sheng","family":"Ho","sequence":"additional","affiliation":[{"name":"Department of Neurology, MacKay Children\u2019s Hospital, Taipei 10449, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e2021053126","DOI":"10.1542\/peds.2021-053126","article-title":"Leukodystrophies in Children: Diagnosis, Care, and Treatment","volume":"148","author":"Bonkowsky","year":"2021","journal-title":"Pediatrics"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1111\/dmcn.13027","article-title":"Leukodystrophies and genetic leukoencephalopathies in childhood: A national epidemiological study","volume":"58","author":"Stellitano","year":"2016","journal-title":"Dev. 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