Doublecortin-like Kinase 1 Regulates ?-Synuclein Levels and Toxicity.

ABSTRACT: ?-Synuclein (?-Syn) accumulation is a pathological hallmark of Parkinson's disease. Duplications and triplications of SNCA, the gene coding for ?-Syn, cause genetic forms of the disease, which suggests that increased ?-Syn dosage can drive PD. To identify the proteins that regulate ?-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 ?-Syn and potential druggability as a neuron-expressed kinase. In this study, we explore the relationship between DCLK1 and ?-Syn in human cellular and mouse models of PD. First, we show that DCLK1 regulates ?-Syn levels post-transcriptionally. Second, we demonstrate that knockdown of Dclk1 reduces phosphorylated species of ?-Syn and ?-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 ?-Syn, thereby highlighting DCLK1 as a potential therapeutic target to reduce pathological ?-Syn in disease.SIGNIFICANCE STATEMENT DCLK1 regulates ?-Syn protein levels, and Dclk1 knockdown rescues ?-Syn toxicity in mice. This study provides evidence for a novel function for DCLK1 in the mature brain, and for its potential as a new therapeutic target for synucleinopathies.

SUBMITTER: Vazquez-Velez GE 

PROVIDER: S-EPMC6948939 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature