{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:22:50Z","timestamp":1792804970225,"version":"4.5.0"},"reference-count":48,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science and Technology Council","award":["NSTC 112-2320-B-007-006"],"award-info":[{"award-number":["NSTC 112-2320-B-007-006"]}]},{"name":"National Science and Technology Council","award":["112-2410-H-182-027"],"award-info":[{"award-number":["112-2410-H-182-027"]}]},{"award":["NSTC 112-2320-B-007-006"],"award-info":[{"award-number":["NSTC 112-2320-B-007-006"]}],"id":[{"id":"https:\/\/ror.org\/00wnb9798","id-type":"ROR","asserted-by":"publisher"}]},{"award":["112-2410-H-182-027"],"award-info":[{"award-number":["112-2410-H-182-027"]}],"id":[{"id":"https:\/\/ror.org\/00wnb9798","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005057","name":"National Tsing Hua University","doi-asserted-by":"crossref","award":["112A2008V6"],"award-info":[{"award-number":["112A2008V6"]}],"id":[{"id":"10.13039\/501100005057","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100005057","name":"National Tsing Hua University","doi-asserted-by":"crossref","award":["113A0117V6"],"award-info":[{"award-number":["113A0117V6"]}],"id":[{"id":"10.13039\/501100005057","id-type":"DOI","asserted-by":"crossref"}]},{"award":["112A2008V6"],"award-info":[{"award-number":["112A2008V6"]}],"id":[{"id":"https:\/\/ror.org\/00zdnkx70","id-type":"ROR","asserted-by":"publisher"}]},{"award":["113A0117V6"],"award-info":[{"award-number":["113A0117V6"]}],"id":[{"id":"https:\/\/ror.org\/00zdnkx70","id-type":"ROR","asserted-by":"publisher"}]},{"name":"BioTEM and the Confocal Imaging Cores at the National Tsing Hua University","award":["NSTC 114-2740-M-007-001"],"award-info":[{"award-number":["NSTC 114-2740-M-007-001"]}],"id":[{"id":"https:\/\/ror.org\/00zdnkx70","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alexander disease (AxD) is a rare and fatal neurodegenerative disorder caused by dominant mutations in the gfap gene, which encodes glial fibrillary acidic protein (GFAP), a major intermediate filament in astrocytes. As a primary astrogliopathy, AxD is marked by white matter abnormalities, the formation of GFAP-containing Rosenthal fibers, astrocyte dysfunction, and progressive neurodegeneration. While GFAP mutations are known to cause toxic gain-of-function effects, the precise mechanisms by which mutant GFAP drives astrocyte dysfunction and central nervous system pathology remain unclear. To address this, we developed a novel rat model of AxD harboring the R237H mutation in the endogenous gfap locus, which mirrors the R239H mutation commonly associated with early-onset AxD in humans. This model recapitulates key AxD pathologies, including GFAP aggregation, widespread astrogliosis, white matter abnormalities, and motor deficits. Using homozygous mutant rats, we dissected the distinct contributions of mutant GFAP and elevated GFAP expression to astrocyte dysfunction and neurodegeneration. Our findings reveal that AxD pathogenesis results from a synergistic interaction between the toxic gain-of-function properties of mutant GFAP and its elevated expression, which together drive GFAP aggregation, proteostatic stress, and astrocyte dysfunction. These insights provide a deeper understanding of AxD mechanisms and a foundation for developing targeted therapies for this devastating disease.<\/jats:p>","DOI":"10.3390\/ijms27104405","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T10:33:21Z","timestamp":1778841201000},"page":"4405","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Synergistic Effects of Glial Fibrillary Acidic Protein Mutation and Overexpression in the Pathogenesis of Alexander Disease"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4524-3615","authenticated-orcid":false,"given":"Ni-Hsuan","family":"Lin","sequence":"first","affiliation":[{"name":"Institute of Molecular Medicine, College of Life Sciences and Medicine, National Tsing Hua University, Hsinchu 30043, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1884-3714","authenticated-orcid":false,"given":"Ming-Der","family":"Perng","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine, College of Life Sciences and Medicine, National Tsing Hua University, Hsinchu 30043, Taiwan"},{"name":"School of Medicine, College of Life Sciences and Medicine, National Tsing Hua University, Hsinchu 30043, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/B978-0-444-64076-5.00044-2","article-title":"Alexander disease","volume":"148","author":"Messing","year":"2018","journal-title":"Handb. 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