T-Type Ca<sup>2+</sup> Enhancer SAK3 Activates CaMKII and Proteasome Activities in Lewy Body Dementia Mice Model

Lewy bodies are pathological characteristics of Lewy body dementia (LBD) and are composed of α-synuclein (α-Syn), which is mostly degraded via the ubiquitin–proteasome system. More importantly, 26S proteasomal activity decreases in the brain of LBD patients. We recently introduced a T-type calcium c...

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Main Authors: Jing Xu, Ichiro Kawahata, Hisanao Izumi, Kohji Fukunaga
Format: Article
Language:English
Published: MDPI AG 2021-06-01
Series:International Journal of Molecular Sciences
Subjects:
Online Access:https://www.mdpi.com/1422-0067/22/12/6185
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spelling doaj-ce332450b6b740d9acc2bde4bf8f28592021-06-30T23:37:14ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-06-01226185618510.3390/ijms22126185T-Type Ca<sup>2+</sup> Enhancer SAK3 Activates CaMKII and Proteasome Activities in Lewy Body Dementia Mice ModelJing Xu0Ichiro Kawahata1Hisanao Izumi2Kohji Fukunaga3Departments of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, JapanDepartments of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, JapanDepartments of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, JapanDepartments of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, JapanLewy bodies are pathological characteristics of Lewy body dementia (LBD) and are composed of α-synuclein (α-Syn), which is mostly degraded via the ubiquitin–proteasome 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’s disease therapeutics. SAK3 enhanced the proteasome activity via CaMKII activation in amyloid precursor protein knock-in mice, promoting the degradation of amyloid-β plaques to improve cognition. At this point, we addressed whether SAK3 promotes the degradation of misfolded α-Syn and the aggregates in α-Syn preformed fibril (PFF)-injected mice. The mice were injected with α-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-α-Syn in the substantia nigra. Accordingly, SAK3 significantly recovered mesencephalic dopamine neurons from cell death. Decreased α-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 α-Syn PFF-injected mice. These findings indicate that CaMKII/Rpt-6-dependent proteasomal activation by SAK3 recovers from α-Syn pathology in LBD.https://www.mdpi.com/1422-0067/22/12/6185alpha-synucleinLewy body dementiaproteasome activityAlzheimer’s diseaseamyloid β plaqueSAK3
collection DOAJ
language English
format Article
sources DOAJ
author Jing Xu
Ichiro Kawahata
Hisanao Izumi
Kohji Fukunaga
spellingShingle Jing Xu
Ichiro Kawahata
Hisanao Izumi
Kohji Fukunaga
T-Type Ca<sup>2+</sup> Enhancer SAK3 Activates CaMKII and Proteasome Activities in Lewy Body Dementia Mice Model
International Journal of Molecular Sciences
alpha-synuclein
Lewy body dementia
proteasome activity
Alzheimer’s disease
amyloid β plaque
SAK3
author_facet Jing Xu
Ichiro Kawahata
Hisanao Izumi
Kohji Fukunaga
author_sort Jing Xu
title T-Type Ca<sup>2+</sup> Enhancer SAK3 Activates CaMKII and Proteasome Activities in Lewy Body Dementia Mice Model
title_short T-Type Ca<sup>2+</sup> Enhancer SAK3 Activates CaMKII and Proteasome Activities in Lewy Body Dementia Mice Model
title_full T-Type Ca<sup>2+</sup> Enhancer SAK3 Activates CaMKII and Proteasome Activities in Lewy Body Dementia Mice Model
title_fullStr T-Type Ca<sup>2+</sup> Enhancer SAK3 Activates CaMKII and Proteasome Activities in Lewy Body Dementia Mice Model
title_full_unstemmed T-Type Ca<sup>2+</sup> Enhancer SAK3 Activates CaMKII and Proteasome Activities in Lewy Body Dementia Mice Model
title_sort t-type ca<sup>2+</sup> enhancer sak3 activates camkii and proteasome activities in lewy body dementia mice model
publisher MDPI AG
series International Journal of Molecular Sciences
issn 1661-6596
1422-0067
publishDate 2021-06-01
description Lewy bodies are pathological characteristics of Lewy body dementia (LBD) and are composed of α-synuclein (α-Syn), which is mostly degraded via the ubiquitin–proteasome 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’s disease therapeutics. SAK3 enhanced the proteasome activity via CaMKII activation in amyloid precursor protein knock-in mice, promoting the degradation of amyloid-β plaques to improve cognition. At this point, we addressed whether SAK3 promotes the degradation of misfolded α-Syn and the aggregates in α-Syn preformed fibril (PFF)-injected mice. The mice were injected with α-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-α-Syn in the substantia nigra. Accordingly, SAK3 significantly recovered mesencephalic dopamine neurons from cell death. Decreased α-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 α-Syn PFF-injected mice. These findings indicate that CaMKII/Rpt-6-dependent proteasomal activation by SAK3 recovers from α-Syn pathology in LBD.
topic alpha-synuclein
Lewy body dementia
proteasome activity
Alzheimer’s disease
amyloid β plaque
SAK3
url https://www.mdpi.com/1422-0067/22/12/6185
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