{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T19:15:34Z","timestamp":1772738134670,"version":"3.50.1"},"reference-count":93,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,3,9]],"date-time":"2023-03-09T00:00:00Z","timestamp":1678320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>Transactive response DNA binding protein-43 (TDP-43) is known to mediate neurodegeneration associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). The exact mechanism by which TDP-43 exerts toxicity in the brains, spinal cord, and lower motor neurons of affected patients remains unclear. In a novel <jats:italic>Drosophila melanogaster<\/jats:italic> model, we report gain-of-function phenotypes due to misexpression of insect codon-optimized version of human wild-type TDP-43 (CO-TDP-43) using both the binary GAL4\/<jats:italic>UAS<\/jats:italic> system and direct promoter fusion constructs. The CO-TDP-43 model showed robust tissue specific phenotypes in the adult eye, wing, and bristles in the notum. Compared to non-codon optimized transgenic flies, the CO-TDP-43 flies produced increased amount of high molecular weight protein, exhibited pathogenic phenotypes, and showed cytoplasmic aggregation with both nuclear and cytoplasmic expression of TDP-43. Further characterization of the adult retina showed a disruption in the morphology and function of the photoreceptor neurons with the presence of acidic vacuoles that are characteristic of autophagy. Based on our observations, we propose that TDP-43 has the propensity to form toxic protein aggregates <jats:italic>via<\/jats:italic> a gain-of-function mechanism, and such toxic overload leads to activation of protein degradation pathways such as autophagy. The novel codon optimized TDP-43 model is an excellent resource that could be used in genetic screens to identify and better understand the exact disease mechanism of TDP-43 proteinopathies and find potential therapeutic targets.<\/jats:p>","DOI":"10.3389\/fgene.2023.881638","type":"journal-article","created":{"date-parts":[[2023,3,9]],"date-time":"2023-03-09T05:56:56Z","timestamp":1678341416000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Codon-optimized TDP-43 mediates neurodegeneration in a Drosophila model of ALS\/FTLD"],"prefix":"10.3389","volume":"14","author":[{"given":"Tanzeen","family":"Yusuff","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ya-Chu","family":"Chang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tzu-Kang","family":"Sang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George R.","family":"Jackson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shreyasi","family":"Chatterjee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,3,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"4947","DOI":"10.1093\/hmg\/ddr432","article-title":"Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation","volume":"20","author":"Ambegaokar","year":"2011","journal-title":"Hum. 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