{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T14:59:54Z","timestamp":1787497194650,"version":"build-2736575974"},"reference-count":48,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2023,9,18]],"date-time":"2023-09-18T00:00:00Z","timestamp":1694995200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Pineal Research"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Huntington's disease (HD) is a progressive neurodegenerative brain disorder associated with uncontrolled body movements, cognitive decline, and reduced circulating melatonin levels. Melatonin is a potent antioxidant and exogenous melatonin treatment is neuroprotective in experimental HD models. In neurons, melatonin is exclusively synthesized in the mitochondrial matrix. Thus, we investigated the integrity of melatonin biosynthesis pathways in pineal and extrapineal brain areas in human HD brain samples, in the R6\/2 mouse model of HD and in full\u2010length mutant huntingtin knock\u2010in cells. Aralkylamine N\u2010acetyltransferase (AANAT) is the rate\u2010limiting step enzyme in the melatonin biosynthetic pathway. We found that AANAT expression is significantly decreased in the pineal gland and the striatum of HD patients compared to normal controls. In the R6\/2 mouse forebrain, AANAT protein expression was decreased in synaptosomal, but not nonsynaptosomal, mitochondria and was associated with decreased synaptosomal melatonin levels compared to wild type mice. We also demonstrate sequestration of AANAT in mutant\u2010huntingtin protein aggregates likely resulting in decreased AANAT bioavailability. Paradoxically,\n                    <jats:italic>AANAT<\/jats:italic>\n                    mRNA expression is increased in tissues where AANAT protein expression is decreased, suggesting a potential feedback loop that is, ultimately unsuccessful. In conclusion, we demonstrate that pineal, extrapineal, and synaptosomal melatonin levels are compromised in the brains of HD patients and R6\/2 mice due, at least in part, to protein aggregation.\n                  <\/jats:p>","DOI":"10.1111\/jpi.12909","type":"journal-article","created":{"date-parts":[[2023,9,18]],"date-time":"2023-09-18T05:48:52Z","timestamp":1695016132000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Biosynthesis of neuroprotective melatonin is dysregulated in Huntington's disease"],"prefix":"10.1111","volume":"75","author":[{"given":"Jinho","family":"Kim","sequence":"first","affiliation":[{"name":"Neuroapoptosis Laboratory, Department of Neurological Surgery University of Pittsburgh School of Medicine  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Li","sequence":"additional","affiliation":[{"name":"Neuroapoptosis Laboratory, Department of Neurological Surgery University of Pittsburgh School of Medicine  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Wang","sequence":"additional","affiliation":[{"name":"Neuroapoptosis Laboratory, Department of Neurological Surgery University of Pittsburgh School of Medicine  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergei V.","family":"Baranov","sequence":"additional","affiliation":[{"name":"Neuroapoptosis Laboratory, Department of Neurological Surgery University of Pittsburgh School of Medicine  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brianna E.","family":"Heath","sequence":"additional","affiliation":[{"name":"Neuroapoptosis Laboratory, Department of Neurological Surgery University of Pittsburgh School of Medicine  Pittsburgh Pennsylvania 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