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Article

T-Type Ca2+ Enhancer SAK3 Activates CaMKII and Proteasome Activities in Lewy Body Dementia Mice Model

1
Departments of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan
2
Departments of CNS Drug Innovation, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan
*
Author to whom correspondence should be addressed.
Academic Editor: Pier Luigi San Biagio
Int. J. Mol. Sci. 2021, 22(12), 6185; https://doi.org/10.3390/ijms22126185
Received: 12 May 2021 / Revised: 1 June 2021 / Accepted: 3 June 2021 / Published: 8 June 2021
(This article belongs to the Special Issue Protein Kinases and Neurodegenerative Diseases)
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. View Full-Text
Keywords: alpha-synuclein; Lewy body dementia; proteasome activity; Alzheimer’s disease; amyloid β plaque; SAK3; T-type Ca2+ channel enhancer alpha-synuclein; Lewy body dementia; proteasome activity; Alzheimer’s disease; amyloid β plaque; SAK3; T-type Ca2+ channel enhancer
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MDPI and ACS Style

Xu, J.; Kawahata, I.; Izumi, H.; Fukunaga, K. T-Type Ca2+ Enhancer SAK3 Activates CaMKII and Proteasome Activities in Lewy Body Dementia Mice Model. Int. J. Mol. Sci. 2021, 22, 6185. https://doi.org/10.3390/ijms22126185

AMA Style

Xu J, Kawahata I, Izumi H, Fukunaga K. T-Type Ca2+ Enhancer SAK3 Activates CaMKII and Proteasome Activities in Lewy Body Dementia Mice Model. International Journal of Molecular Sciences. 2021; 22(12):6185. https://doi.org/10.3390/ijms22126185

Chicago/Turabian Style

Xu, Jing, Ichiro Kawahata, Hisanao Izumi, and Kohji Fukunaga. 2021. "T-Type Ca2+ Enhancer SAK3 Activates CaMKII and Proteasome Activities in Lewy Body Dementia Mice Model" International Journal of Molecular Sciences 22, no. 12: 6185. https://doi.org/10.3390/ijms22126185

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