Doublecortin like kinase 1 regulates α-Synuclein levels and toxicity

Journal article

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 substantia nigra in two distinct mouse models of synucleinopathy. Lastly, 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 STATEMENTDCLK1 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.

Authors: Vázquez-Vélez, GE; Gonzales, KA; Revelli, J-P; Adamski, CJ; Naini, F

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Society for Nueroscience
• Journal: Journal of Neuroscience
• Volume: 1076
• Article number: 19
• Publication date: 2019-11-20
• Acceptance date: 2019-10-25
• DOI: 10.1523/jneurosci.1076-19.2019
• EISSN: 1529-2401
• ISSN: 0270-6474
• Pmid: 31748376
• Language: English