{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T01:22:33Z","timestamp":1773624153300,"version":"3.50.1"},"reference-count":66,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,6,8]],"date-time":"2021-06-08T00:00:00Z","timestamp":1623110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Lewy bodies are pathological characteristics of Lewy body dementia (LBD) and are composed of \u03b1-synuclein (\u03b1-Syn), which is mostly degraded via the ubiquitin\u2013proteasome system. More importantly, 26S proteasomal activity decreases in the brain of LBD patients. We recently introduced a T-type calcium channel enhancer SAK3 (ethyl-8-methyl-2,4-dioxo-2-(piperidin-1-yl)- 2H-spiro[cyclopentane-1,3-imidazo [1,2-a]pyridin]-2-ene-3-carboxylate) for Alzheimer\u2019s disease therapeutics. SAK3 enhanced the proteasome activity via CaMKII activation in amyloid precursor protein knock-in mice, promoting the degradation of amyloid-\u03b2 plaques to improve cognition. At this point, we addressed whether SAK3 promotes the degradation of misfolded \u03b1-Syn and the aggregates in \u03b1-Syn preformed fibril (PFF)-injected mice. The mice were injected with \u03b1-Syn PFF in the dorsal striatum, and SAK3 (0.5 or 1.0 mg\/kg) was administered orally for three months, either immediately or during the last month after injection. SAK3 significantly inhibited the accumulation of fibrilized phosphorylated-\u03b1-Syn in the substantia nigra. Accordingly, SAK3 significantly recovered mesencephalic dopamine neurons from cell death. Decreased \u03b1-Syn accumulation was closely associated with increased proteasome activity. Elevated CaMKII\/Rpt-6 signaling possibly mediates the enhanced proteasome activity after SAK3 administration in the cortex and hippocampus. CaMKII\/Rpt-6 activation also accounted for improved memory and cognition in \u03b1-Syn PFF-injected mice. These findings indicate that CaMKII\/Rpt-6-dependent proteasomal activation by SAK3 recovers from \u03b1-Syn pathology in LBD.<\/jats:p>","DOI":"10.3390\/ijms22126185","type":"journal-article","created":{"date-parts":[[2021,6,8]],"date-time":"2021-06-08T12:08:55Z","timestamp":1623154135000},"page":"6185","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["T-Type Ca2+ Enhancer SAK3 Activates CaMKII and Proteasome Activities in Lewy Body Dementia Mice Model"],"prefix":"10.3390","volume":"22","author":[{"given":"Jing","family":"Xu","sequence":"first","affiliation":[{"name":"Departments of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5916-7847","authenticated-orcid":false,"given":"Ichiro","family":"Kawahata","sequence":"additional","affiliation":[{"name":"Departments of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan"},{"name":"Departments of CNS Drug Innovation, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hisanao","family":"Izumi","sequence":"additional","affiliation":[{"name":"Departments of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8526-2824","authenticated-orcid":false,"given":"Kohji","family":"Fukunaga","sequence":"additional","affiliation":[{"name":"Departments of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan"},{"name":"Departments of CNS Drug Innovation, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1136\/jnnp.52.2.201","article-title":"Does cognitive impairment in Parkinson\u2019s disease result from non-dopaminergic lesions?","volume":"52","author":"Pillon","year":"1989","journal-title":"J. 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