Doublecortin-like Kinase 1 Regulates α-Synuclein Levels and Toxicity
Summary
α-Synuclein (α-Syn) accumulation is a pathological hallmark of Parkinson's disease. Duplications and triplications of SNCA, the gene coding for α-Syn, cause genetic forms of the disease, which suggests that increased α-Syn dosage can drive PD. To identify the proteins that regulate α-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 α-Syn and potential druggability as a neuron-expressed kinase. In this study, we explore the relationship between DCLK1 and α-Syn in human cellular and mouse models of PD. First, we show that DCLK1 regulates α-Syn levels post-transcriptionally. Second, we demonstrate that knockdown of Dclk1 reduces phosphorylated species of α-Syn and α-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 α-Syn, thereby highlighting DCLK1 as a potential therapeutic target to reduce pathological α-Syn in disease.SIGNIFICANCE STATEMENT DCLK1 regulates α-Syn protein levels, and Dclk1 knockdown rescues α-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. Copyright © 2020 the authors.
| Authors | Vázquez-Vélez GE, Gonzales KA, Revelli JP, Adamski CJ, Alavi Naini F, Bajić A, Craigen E, Richman R, Heman-Ackah SM, Wood MJA, Rousseaux MWC, Zoghbi HY |
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| Journal | The Journal of neuroscience : the official journal of the Society for Neuroscience |
| Publication Date | 2020 Jan 8;40(2):459-477 |
| PubMed | 31748376 |
| PubMed Central | PMC6948939 |
| DOI | 10.1523/jneurosci.1076-19.2019 |