RT Journal Article
SR Electronic
T1 Doublecortin like kinase 1 regulates α-Synuclein levels and toxicity
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 1076-19
DO 10.1523/JNEUROSCI.1076-19.2019
A1 Gabriel E. Vázquez-Vélez
A1 Kristyn A. Gonzales
A1 Jean-Pierre Revelli
A1 Carolyn J. Adamski
A1 Fatemeh Alavi Naini
A1 Aleksandar Bajić
A1 Evelyn Craigen
A1 Ronald Richman
A1 Sabrina M. Heman-Ackah
A1 Matthew J.A. Wood
A1 Maxime W.C. Rousseaux
A1 Huda Y. Zoghbi
YR 2019
UL http://www.jneurosci.org/content/early/2019/11/20/JNEUROSCI.1076-19.2019.abstract
AB 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.