Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 12, Pages -Publisher
MDPI
DOI: 10.3390/ijms22126185
Keywords
alpha-synuclein; Lewy body dementia; proteasome activity; Alzheimer's disease; amyloid beta plaque; SAK3; T-type Ca2+ channel enhancer
Funding
- Strategic Research Program for Brain Sciences from the Japan Agency for Medical Research and Development [JP17dm0107071, JP18dm0107071, JP19dm0107071, JP20dm0107071]
- Smoking Research Foundation
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SAK3 activates CaMKII to enhance proteasomal activity, leading to the degradation of α-Syn and slowing down the progression of LBD. This study reveals the promoting effect of SAK3 on α-Syn pathology.
Lewy bodies are pathological characteristics of Lewy body dementia (LBD) and are composed of alpha-synuclein (alpha-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-beta plaques to improve cognition. At this point, we addressed whether SAK3 promotes the degradation of misfolded alpha-Syn and the aggregates in alpha-Syn preformed fibril (PFF)-injected mice. The mice were injected with alpha-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-alpha-Syn in the substantia nigra. Accordingly, SAK3 significantly recovered mesencephalic dopamine neurons from cell death. Decreased alpha-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 alpha-Syn PFF-injected mice. These findings indicate that CaMKII/Rpt-6-dependent proteasomal activation by SAK3 recovers from alpha-Syn pathology in LBD.
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