For example, certain mutations in the α-Syn-encoding SNCA gene or SNCA duplication/triplication cause familial PD. α-Syn abundance appears to be causatively linked to these pathologies. These include Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Aggregated α-Syn represents the pathological hallmark of so-called α-synucleinopathies. α-Synuclein ( α-Syn) is a soluble, presynaptic protein that is found abundantly in neuronal presynapses throughout the brain. Accordingly, CK1BP represents a promising target for the rational design of therapeutic approaches to cease or at least delay the progression of α-synucleinopathies.Ībnormal protein deposition in the central nervous system (CNS) is a common pathologic feature of many neurodegenerative diseases (NDDs). Our results imply that the inhibition of CK1 activity by CK1BP might exert beneficial effects on NDDs in general. Further analysis of an aggregating polyglutamine (polyQ) protein confirmed a phosphorylation-independent decrease in aggregation. Analyzing different α-Syn variants including S129 mutations, we show that the effects of CK1BP on α-Syn accumulation were independent of S129 phosphorylation. Moreover, CK1BP concomitantly reduced S129 phosphorylation, oligomerization and the amount of insoluble α-Syn. We found that CK1BP reduced the overall protein levels of α-Syn. Using Bimolecular Fluorescence Complementation (BiFC) in combination with biochemical methods, we monitored the S129 phosphorylation and oligomerization of α-Syn in HEK293T cells.
We overexpressed CK1 binding protein (CK1BP) to inhibit CK1 kinase activity. Among other kinases, protein kinase CK1 (CK1) is known to phosphorylate α-Syn at S129. Therefore, S129-phosphorylation is suspected to interfere with α-Syn aggregation. In contrast to the mostly non-phosphorylated soluble α-Syn, aggregated α-Syn is usually phosphorylated at serine 129 (S129). The pathological accumulation of α-Synuclein ( α-Syn) is the hallmark of neurodegenerative α-synucleinopathies, including Parkinsons’s disease (PD).
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