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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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 |
work_keys_str_mv |
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