{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T15:25:41Z","timestamp":1791213941973,"version":"4.1.0"},"reference-count":46,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2014,12,16]],"date-time":"2014-12-16T00:00:00Z","timestamp":1418688000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Life Extension Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2015,2]]},"abstract":"<jats:title>Summary<\/jats:title>\n                  <jats:p>\n                    Age\u2010dependent neurodegenerative diseases progressively form aggregates containing both shared components (e.g.,\n                    <jats:styled-content style=\"fixed-case\">TDP<\/jats:styled-content>\n                    \u201043, phosphorylated tau) and proteins specific to each disease. We investigated whether diverse neuropathies might have additional aggregation\u2010prone proteins in common, discoverable by proteomics.\n                    <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    expressing\n                    <jats:italic>unc\u201054p<\/jats:italic>\n                    \/Q40::\n                    <jats:styled-content style=\"fixed-case\">YFP<\/jats:styled-content>\n                    , a model of polyglutamine array diseases such as Huntington's, accrues aggregates in muscle 2\u20136\u00a0days posthatch. These foci, isolated on antibody\u2010coupled magnetic beads, were characterized by high\u2010resolution mass spectrometry. Three Q40::\n                    <jats:styled-content style=\"fixed-case\">YFP<\/jats:styled-content>\n                    \u2010associated proteins were inferred to promote aggregation and cytotoxicity, traits reduced or delayed by their\n                    <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>\n                    interference knockdown. These\n                    <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>\n                    i treatments also retarded aggregation\/cytotoxicity in Alzheimer's disease models, nematodes with muscle or pan\u2010neuronal A\u03b2\n                    <jats:sub>1\u201342<\/jats:sub>\n                    expression and behavioral phenotypes. The most abundant aggregated proteins are glutamine\/asparagine\u2010rich, favoring hydrophobic interactions with other random\u2010coil domains. A particularly potent modulator of aggregation,\n                    <jats:styled-content style=\"fixed-case\">CRAM<\/jats:styled-content>\n                    \u20101\/\n                    <jats:styled-content style=\"fixed-case\">HYPK<\/jats:styled-content>\n                    , contributed &lt;\u00a01% of protein aggregate peptides, yet its knockdown reduced Q40::\n                    <jats:styled-content style=\"fixed-case\">YFP<\/jats:styled-content>\n                    aggregates 72\u201286% (\n                    <jats:italic>P\u00a0<\/jats:italic>\n                    &lt;\u00a010\n                    <jats:sup>\u22126<\/jats:sup>\n                    ). In worms expressing A\u03b2\n                    <jats:sub>1\u201342<\/jats:sub>\n                    , knockdown of\n                    <jats:italic>cram\u20101<\/jats:italic>\n                    reduced \u03b2\u2010amyloid 60% (\n                    <jats:italic>P\u00a0<\/jats:italic>\n                    &lt;\u00a00.002) and slowed age\u2010dependent paralysis &gt;\u00a030% (\n                    <jats:italic>P\u00a0<\/jats:italic>\n                    &lt;\u00a010\n                    <jats:sup>\u22126<\/jats:sup>\n                    ). In wild\u2010type worms,\n                    <jats:italic>cram\u20101<\/jats:italic>\n                    knockdown reduced aggregation and extended lifespan, but impaired early reproduction. Protection against seeded aggregates requires proteasome function, implying that normal\n                    <jats:styled-content style=\"fixed-case\">CRAM<\/jats:styled-content>\n                    \u20101 levels promote aggregation by interfering with proteasomal degradation of misfolded proteins. Molecular dynamic modeling predicts spontaneous and stable interactions of\n                    <jats:styled-content style=\"fixed-case\">CRAM<\/jats:styled-content>\n                    \u20101 (or human orthologs) with ubiquitin, and we verified that\n                    <jats:styled-content style=\"fixed-case\">CRAM<\/jats:styled-content>\n                    \u20101 reduces degradation of a tagged\u2010ubiquitin reporter. We propose that\n                    <jats:styled-content style=\"fixed-case\">CRAM<\/jats:styled-content>\n                    \u20101 exemplifies a class of primitive chaperones that are initially protective and highly beneficial for early reproduction, but ultimately impair aggregate clearance and limit longevity.\n                  <\/jats:p>","DOI":"10.1111\/acel.12296","type":"journal-article","created":{"date-parts":[[2014,12,16]],"date-time":"2014-12-16T05:57:13Z","timestamp":1418709433000},"page":"35-48","source":"Crossref","is-referenced-by-count":57,"title":["Proteins in aggregates functionally impact multiple neurodegenerative disease models by forming proteasome\u2010blocking complexes"],"prefix":"10.1111","volume":"14","author":[{"given":"Srinivas","family":"Ayyadevara","sequence":"first","affiliation":[{"name":"McClellan Veterans Medical Center Central Arkansas Veterans Healthcare Service Little Rock AR 72205 USA"},{"name":"Department of Geriatrics University of Arkansas for Medical Sciences Little Rock AR 72205 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meenakshisundaram","family":"Balasubramaniam","sequence":"additional","affiliation":[{"name":"Department of Geriatrics University of Arkansas for Medical Sciences Little Rock AR 72205 USA"},{"name":"BioInformatics Program University of Arkansas for Medical Sciences and University of Arkansas at Little Rock Little Rock AR 72205 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Gao","sequence":"additional","affiliation":[{"name":"National Center for Toxicological Research Food &amp; Drug Administration Jefferson AR 72079 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li\u2010Rong","family":"Yu","sequence":"additional","affiliation":[{"name":"National Center for Toxicological Research Food &amp; Drug Administration Jefferson AR 72079 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramani","family":"Alla","sequence":"additional","affiliation":[{"name":"McClellan Veterans Medical Center Central Arkansas Veterans Healthcare Service Little Rock AR 72205 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Shmookler Reis","sequence":"additional","affiliation":[{"name":"McClellan Veterans Medical Center Central Arkansas Veterans Healthcare Service Little Rock AR 72205 USA"},{"name":"Department of Geriatrics University of Arkansas for Medical Sciences Little Rock AR 72205 USA"},{"name":"Department of Biochemistry &amp; Molecular Biology University of Arkansas for Medical Sciences Little Rock AR 72205 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,12,16]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01199-09"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2011.12.013"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2011.4151"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000414"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature06022"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0902882106"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2013.00034"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12031-011-9545-z"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1463"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0096835"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1474-9726.2009.00541.x"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1000450"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.2010.0271"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0058893"},{"key":"e_1_2_9_16_1","doi-asserted-by":"crossref","first-page":"681","DOI":"10.3233\/JAD-2010-1267","article-title":"Behavioral phenotyping of a transgenic Caenorhabditis elegans expressing neuronal amyloid\u2010beta","volume":"19","author":"Dosanjh LE","year":"2010","journal-title":"J. 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