{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T14:08:08Z","timestamp":1777644488636,"version":"3.51.4"},"reference-count":100,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,8]],"date-time":"2022-11-08T00:00:00Z","timestamp":1667865600000},"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. Mol. Neurosci."],"abstract":"<jats:p>Huntington\u2019s disease occurs when the stretch of CAG repeats in exon 1 of the <jats:italic>huntingtin<\/jats:italic> (<jats:italic>htt<\/jats:italic>) gene crosses the permissible limit, causing the mutated protein (mHtt) to form insoluble aggregates or inclusion bodies. These aggregates are non-typically associated with various essential proteins in the cells, thus disrupting cellular homeostasis. The cells try to bring back normalcy by synthesizing evolutionary conserved cellular chaperones, and Hsp70 is one of the families of heat shock proteins that has a significant part in this, which comprises of heat-inducible and cognate forms. Here, we demonstrate that the heat shock cognate (Hsc70) isoform, Hsc70-4\/HSPA8, has a distinct role in polyglutamate (PolyQ)-mediated pathogenicity, and its expression is enhanced in the <jats:italic>polyQ<\/jats:italic> conditions in <jats:italic>Drosophila<\/jats:italic>. Downregulation of <jats:italic>hsc70-4<\/jats:italic> rescues PolyQ pathogenicity with a notable improvement in the ommatidia arrangement and near-normal restoration of optic neurons leading to improvement in phototaxis response. Reduced <jats:italic>hsc70-4<\/jats:italic> also attenuates the augmented immune response by decreasing the expression of NF-\u03baB and the antimicrobial peptides, along with that JNK overactivation is also restored. These lead to the rescue of the photoreceptor cells, indicating a decrease in the caspase activity, thus reverting the PolyQ pathogenicity. At the molecular level, we show the interaction between Hsc70-4, Polyglutamine aggregates, and NF-\u03baB, which may be responsible for the dysregulation of signaling molecules in <jats:italic>polyQ<\/jats:italic> conditions. Thus, the present data provides a functional link between Hsc70-4 and NF-\u03baB under <jats:italic>polyQ<\/jats:italic> conditions.<\/jats:p>","DOI":"10.3389\/fnmol.2022.857257","type":"journal-article","created":{"date-parts":[[2022,11,8]],"date-time":"2022-11-08T04:43:05Z","timestamp":1667882585000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Hsc70-4 aggravates PolyQ-mediated neurodegeneration by modulating NF-\u03baB mediated immune response in Drosophila"],"prefix":"10.3389","volume":"15","author":[{"given":"Saurabh","family":"Rai","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madhu G.","family":"Tapadia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1042\/BJ20050412","article-title":"Heat-shock cognate 70 is required for the activation of heat-shock factor 1 in mammalian cells.","volume":"392","author":"Ahn","year":"2005","journal-title":"Biochem. 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