{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:51:17Z","timestamp":1790614277591,"version":"4.1.0"},"reference-count":116,"publisher":"Oxford University Press (OUP)","issue":"14","license":[{"start":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T00:00:00Z","timestamp":1679875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Italian Minister for Research and University","award":["20177XJCHX"],"award-info":[{"award-number":["20177XJCHX"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,7,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Conformational diseases, such as Alzheimer, Parkinson and Huntington diseases, are part of a common class of neurological disorders characterized by the aggregation and progressive accumulation of proteins bearing aberrant conformations. Huntington disease (HD) has autosomal dominant inheritance and is caused by mutations leading to an abnormal expansion in the polyglutamine (polyQ) tract of the huntingtin (HTT) protein, leading to the formation of HTT inclusion bodies in neurons of affected patients. Interestingly, recent experimental evidence is challenging the conventional view by which the disease pathogenesis is solely a consequence of the intracellular accumulation of mutant protein aggregates. These studies reveal that transcellular transfer of mutated huntingtin protein is able to seed oligomers involving even the wild-type (WT) forms of the protein. To date, there is still no successful strategy to treat HD. Here, we describe a novel functional role for the HSPB1-p62\/SQSTM1 complex, which acts as a cargo loading platform, allowing the unconventional secretion of mutant HTT by extracellular vesicles. HSPB1 interacts preferentially with polyQ-expanded HTT compared with the WT protein and affects its aggregation. Furthermore, HSPB1 levels correlate with the rate of mutant HTT secretion, which is controlled by the activity of the PI3K\/AKT\/mTOR signalling pathway. Finally, we show that these HTT-containing vesicular structures are biologically active and able to be internalized by recipient cells, therefore providing an additional mechanism to explain the prion-like spreading properties of mutant HTT. These findings might also have implications for the turn-over of other disease-associated, aggregation-prone proteins.<\/jats:p>","DOI":"10.1093\/hmg\/ddad047","type":"journal-article","created":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T13:18:08Z","timestamp":1679923088000},"page":"2269-2291","source":"Crossref","is-referenced-by-count":18,"title":["The HSPB1-p62\/SQSTM1 functional complex regulates the unconventional secretion and transcellular spreading of the HD-associated mutant huntingtin protein"],"prefix":"10.1093","volume":"32","author":[{"given":"R","family":"Bonavita","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnologies, University of Naples \u201cFederico II\u201d , 80131 Naples , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G","family":"Scerra","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnologies, University of Naples \u201cFederico II\u201d , 80131 Naples , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R","family":"Di Martino","sequence":"additional","affiliation":[{"name":"Institute for Endocrinology and Experimental Oncology \u201cG. Salvatore ,\u201d National Research Council, 80131 Naples, Italy"},{"name":"Institute of Biochemistry and Cell Biology, National Research Council , 80131 Naples , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Nuzzo","sequence":"additional","affiliation":[{"name":"IRCCS SYNLAB SDN , 80143 Naples , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E","family":"Polishchuk","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM) , 80078 Pozzuoli , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Di Gennaro","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnologies, University of Naples \u201cFederico II\u201d , 80131 Naples , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S V","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Physiology , Development and Neuroscience, , CB2 3DY Cambridge , UK"},{"name":"University of Cambridge , Development and Neuroscience, , CB2 3DY Cambridge , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M G","family":"Caporaso","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnologies, University of Naples \u201cFederico II\u201d , 80131 Naples , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Caiazza","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnologies, University of Naples \u201cFederico II\u201d , 80131 Naples , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R","family":"Polishchuk","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM) , 80078 Pozzuoli , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"D\u2019Agostino","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnologies, University of Naples \u201cFederico II\u201d , 80131 Naples , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Fleming","sequence":"additional","affiliation":[{"name":"Department of Physiology , Development and Neuroscience, , CB2 3DY Cambridge , UK"},{"name":"University of Cambridge , Development and Neuroscience, , CB2 3DY Cambridge , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Renna","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnologies, University of Naples \u201cFederico II\u201d , 80131 Naples , Italy"},{"name":"Department of Physiology , Development and Neuroscience, , CB2 3DY Cambridge , UK"},{"name":"University of Cambridge , Development and Neuroscience, , CB2 3DY Cambridge , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,3,27]]},"reference":[{"key":"2023070515082724700_ref1","first-page":"98","article-title":"Exosome\/microvesicle-mediated epigenetic reprogramming of cells","volume":"1","author":"Camussi","year":"2011","journal-title":"Am. 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