CK1BP Reduces α-Synuclein Oligomerization and Aggregation Independent of Serine 129 Phosphorylation

The pathological accumulation of [Formula: see text]-Synuclein ([Formula: see text]-Syn) is the hallmark of neurodegenerative [Formula: see text]-synucleinopathies, including Parkinsons’s disease (PD). In contrast to the mostly non-phosphorylated soluble [Formula: see text]-Syn, aggregated [Formula: see text]-Syn is usually phosphorylated at serine 129 (S129). Therefore, S129-phosphorylation is suspected to interfere with [Formula: see text]-Syn aggregation. Among other kinases, protein kinase CK1 (CK1) is known to phosphorylate [Formula: see text]-Syn at S129. We overexpressed CK1 binding protein (CK1BP) to inhibit CK1 kinase activity. Using Bimolecular Fluorescence Complementation (BiFC) in combination with biochemical methods, we monitored the S129 phosphorylation and oligomerization of [Formula: see text]-Syn in HEK293T cells. We found that CK1BP reduced the overall protein levels of [Formula: see text]-Syn. Moreover, CK1BP concomitantly reduced S129 phosphorylation, oligomerization and the amount of insoluble [Formula: see text]-Syn. Analyzing different [Formula: see text]-Syn variants including S129 mutations, we show that the effects of CK1BP on [Formula: see text]-Syn accumulation were independent of S129 phosphorylation. Further analysis of an aggregating polyglutamine (polyQ) protein confirmed a phosphorylation-independent decrease in aggregation. Our results imply that the inhibition of CK1 activity by CK1BP might exert beneficial effects on NDDs in general. Accordingly, CK1BP represents a promising target for the rational design of therapeutic approaches to cease or at least delay the progression of [Formula: see text]-synucleinopathies.