Doublecortin-like Kinase 1 Regulates α-Synuclein Levels and Toxicity

alpha-Synuclein (alpha-Syn) accumulation is a pathological hallmark of Parkinson's disease. Duplications and triplications of SNCA, the gene coding for alpha-Syn, cause genetic forms of the disease, which suggests that increased alpha-Syn dosage can drive PD. To identify the proteins that regulate alpha-Syn, we previously performed a screen of potentially druggable genes that led to the identification of 60 modifiers. Among them, Doublecortin-like kinase 1 (DCLK1), a microtubule binding serine threonine kinase, emerged as a promising target due to its potent effect on alpha-Syn and potential druggability as a neuron-expressed kinase. In this study, we explore the relationship between DCLK1 and alpha-Syn in human cellular and mouse models of PD. First, we show that DCLK1 regulates alpha-Syn levels post-transcriptionally. Second, we demonstrate that knockdown of Dclk1 reduces phosphorylated species of alpha-Syn and alpha-Syn-induced neurotoxicity in the SNc in two distinct mouse models of synucleinopathy. Last, silencing DCLK1 in human neurons derived from individuals with SNCA triplications reduces phosphorylated and total alpha-Syn, thereby highlighting DCLK1 as a potential therapeutic target to reduce pathological alpha-Syn in disease.