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In eukaryotes, its ATP\/ADP nucleotide exchange cycle is stimulated by co-chaperone Hsp110, a divergent Hsp70 superfamily member and a modifier of protein misfolding disorders. Hsp110 chaperone functions and pathway interactions have been extensively characterized biochemically in vitro and genetically in yeast models; however, its physiological roles in metazoans, particularly in the nervous system, are lacking. Here, we showed that the single Hsp110 gene in Drosophila shares significant sequence, structural, and splicing-variant similarities with human Hsp110. In Drosophila, Hsp110 is ubiquitously expressed and dispensable for cell proliferation in developing larvae but is essential for long-term cell survival and nervous system development, including nonautonomous effects on neuronal differentiation and glial cell migration. Furthermore, loss of Hsp110 leads to abnormal accumulation of ubiquitin-positive inclusions in the brain. Lastly, despite being identified as a potent suppressor of protein aggregation and neurotoxicity in neurodegenerative diseases, higher levels of Hsp110 are detrimental in flies. Overexpression of Hsp40, another key co-chaperone of Hsp70, can mimic this effect. However, simultaneous overexpression of both Hsp40 and Hsp110 does not further exacerbate their detrimental effect. Together, these results demonstrate a critical role of Hsp110 in cellular proteostasis, neuronal development, and cell survival in metazoans, and suggest that in vivo, the levels and activities of Hsp110 and Hsp40 co-chaperones need to be properly balanced, and the Hsp70 chaperone network should be considered as a whole when targeted for potential therapeutic purposes to meet the complex pathophysiological demands in multicellular organisms.<\/jats:p>","DOI":"10.1093\/genetics\/iyag240","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T06:13:07Z","timestamp":1788761587000},"source":"Crossref","is-referenced-by-count":0,"title":["Nervous system integrity in\n                    <i>Drosophila<\/i>\n                    : essential and dosage-sensitive roles of Hsp110"],"prefix":"10.1093","author":[{"given":"Beatriz","family":"Rios","sequence":"first","affiliation":[{"name":"Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth Houston) , Houston, TX 77030 ,","place":["United States"]},{"name":"Program in Neuroscience, The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences (MD Anderson UTHealth Houston GSBS) , Houston, TX 77030 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyu","family":"Xu","sequence":"additional","affiliation":[{"name":"Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth Houston) , Houston, TX 77030 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen M","family":"Farmer","sequence":"additional","affiliation":[{"name":"Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth Houston) , Houston, TX 77030 ,","place":["United States"]},{"name":"Program in Neuroscience, The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences (MD Anderson UTHealth Houston GSBS) , Houston, TX 77030 ,","place":["United States"]},{"name":"Program in Molecular and Translational Biology, The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences (MD Anderson UTHealth Houston GSBS) , Houston, TX 77030 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Ye","sequence":"additional","affiliation":[{"name":"Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth Houston) , Houston, TX 77030 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Ye","sequence":"additional","affiliation":[{"name":"Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth Houston) , Houston, TX 77030 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5992-0253","authenticated-orcid":false,"given":"Kevin A","family":"Morano","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth Houston) , Houston, TX 77030 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6015-2960","authenticated-orcid":false,"given":"Sheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth Houston) , Houston, TX 77030 ,","place":["United States"]},{"name":"Program in Genetics and Epigenetics, The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences (MD Anderson UTHealth Houston GSBS) , Houston, TX 77030 ,","place":["United States"]},{"name":"Department of Neurobiology and Anatomy, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth Houston) , Houston, TX 77030 ,","place":["United 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