{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T02:29:14Z","timestamp":1791080954738,"version":"4.1.0"},"reference-count":41,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2006,6,19]],"date-time":"2006-06-19T00:00:00Z","timestamp":1150675200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2006,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In Huntington's disease (HD), as in the rest of CAG triplet\u2010repeat disorders, the expanded polyglutamine (polyQ)\u2010containing proteins form intraneuronal fibrillar aggregates that are gathered into inclusion bodies (IBs). Since IBs contain ubiquitin and proteasome subunits, it was proposed that inhibition of proteasome activity might underlie pathogenesis of polyQ disorders. Recent <jats:italic>in vitro<\/jats:italic> enzymatic studies revealed the inability of eukaryotic proteasomes to digest expanded polyQ, thus suggesting that occasional failure of polyQ to exit the proteasome may interfere with its proteolytic function. However, it has also recently been found that <jats:italic>in vitro<\/jats:italic> assembled aggregates made of synthetic polyQ fail to inhibit proteasome activity. Because synthetic polyQ aggregates lack the post\u2010translational modifications found inside affected neurons, such as poly ubiquitylation, we decided to study the effect of mutant huntingtin (htt) aggregates isolated from the Tet\/HD94 mouse model and from human HD brain tissue. Here, we show that isolated ubiquitylated filamentous htt aggregates, extracted from IBs by a previously reported method, selectively inhibited the <jats:italic>in vitro<\/jats:italic> peptidase activity of the 26S but not of the 20S proteasome in a non\u2010competitive manner. In good agreement, immuno\u2010electron microscopy revealed a direct interaction of htt filaments with the 19S ubiquitin\u2010interacting regulatory caps of the 26S proteasome. Here, we also report a new method for isolation of IBs based on magnetic sorting. Interestingly, isolated IBs did not modify proteasome activity. Our results therefore show that mutant htt filamentous aggregates can inhibit proteasome activity, but only when not recruited into IBs, thus strengthening the notion that IB formation is protective by neutralizing toxicity of dispersed filamentous htt aggregates.<\/jats:p>","DOI":"10.1111\/j.1471-4159.2006.03968.x","type":"journal-article","created":{"date-parts":[[2006,6,19]],"date-time":"2006-06-19T10:26:53Z","timestamp":1150712813000},"page":"1585-1596","source":"Crossref","is-referenced-by-count":79,"title":["Inhibition of 26S proteasome activity by huntingtin filaments but not inclusion bodies isolated from mouse and human brain"],"prefix":"10.1111","volume":"98","author":[{"given":"Miguel","family":"D\u00edaz\u2010Hern\u00e1ndez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana G.","family":"Valera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda A.","family":"Mor\u00e1n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pilar","family":"G\u00f3mez\u2010Ramos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Alvarez\u2010Castelao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 G.","family":"Casta\u00f1o","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F\u00e9lix","family":"Hern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 J.","family":"Lucas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2006,6,19]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature02998"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.292.5521.1552"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2004.12.021"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi064"},{"key":"e_1_2_7_6_1","volume-title":"The Enzymes","author":"Boyer P.","year":"1970"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.6.2727"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/502"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80513-9"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.32.22123"},{"key":"e_1_2_7_11_1","doi-asserted-by":"crossref","first-page":"11\u2003653","DOI":"10.1523\/JNEUROSCI.23-37-11653.2003","article-title":"Neuronal induction of the immunoproteasome in Huntington's disease","volume":"23","author":"Diaz\u2010Hernandez M.","year":"2003","journal-title":"J. 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