{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T12:01:27Z","timestamp":1783166487236,"version":"3.54.6"},"posted":{"date-parts":[[2023,7,3]]},"group-title":"Physiology","reference-count":84,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,7,3]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>\n                  Loss of proteostasis is a hallmark of aging and Alzheimer disease (AD). Here, we identify \u03b2-hydroxybutyrate (\u03b2HB), a ketone body, as a regulator of protein solubility in the aging brain. \u03b2HB is a small molecule metabolite which primarily provides an oxidative substrate for ATP during hypoglycemic conditions, and also regulates other cellular processes through covalent and noncovalent protein interactions. We demonstrate \u03b2HB-induced protein insolubility across\n                  <jats:italic>in vitro<\/jats:italic>\n                  ,\n                  <jats:italic>ex vivo<\/jats:italic>\n                  , and\n                  <jats:italic>in vivo<\/jats:italic>\n                  mouse systems. This activity is shared by select structurally similar metabolites, is not dependent on covalent protein modification, pH, or solute load, and is observable in mouse brain\n                  <jats:italic>in vivo<\/jats:italic>\n                  after delivery of a ketone ester. Furthermore, this phenotype is selective for pathological proteins such as amyloid-\u03b2, and exogenous \u03b2HB ameliorates pathology in nematode models of amyloid-\u03b2 aggregation toxicity. We have generated a comprehensive atlas of the \u03b2HB-induced protein insolublome\n                  <jats:italic>ex vivo<\/jats:italic>\n                  and\n                  <jats:italic>in vivo<\/jats:italic>\n                  using mass spectrometry proteomics, and have identified common protein domains within \u03b2HB target sequences. Finally, we show enrichment of neurodegeneration-related proteins among \u03b2HB targets and the clearance of these targets from mouse brain, likely via \u03b2HB-induced autophagy. Overall, these data indicate a new metabolically regulated mechanism of proteostasis relevant to aging and AD.\n                <\/jats:p>","DOI":"10.1101\/2023.07.03.547547","type":"posted-content","created":{"date-parts":[[2023,7,4]],"date-time":"2023-07-04T02:45:20Z","timestamp":1688438720000},"source":"Crossref","is-referenced-by-count":2,"title":["\u03b2-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer disease brain"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8163-0917","authenticated-orcid":false,"given":"SS","family":"Madhavan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Roa Diaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Peralta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1811-4917","authenticated-orcid":false,"given":"M","family":"Nomura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"CD","family":"King","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D","family":"Bhaumik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Shah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T","family":"Blade","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W","family":"Gray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Chamoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6457-2436","authenticated-orcid":false,"given":"B","family":"Eap","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"O","family":"Panda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D","family":"Diaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"TY","family":"Garcia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"BJ","family":"Stubbs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"GJ","family":"Lithgow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9907-2749","authenticated-orcid":false,"given":"B","family":"Schilling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E","family":"Verdin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"AR","family":"Chaudhuri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8455-0100","authenticated-orcid":false,"given":"JC","family":"Newman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2023071205254841000_2023.07.03.547547v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0235-9"},{"key":"2023071205254841000_2023.07.03.547547v1.2","doi-asserted-by":"crossref","unstructured":"Goedert, M . 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