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

J Neurosci. 2020 Jan 8;40(2):459-477. doi: 10.1523/JNEUROSCI.1076-19.2019. Epub 2019 Nov 20.


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.

Keywords: DCLK1; disease models; protein levels; α-synuclein.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Doublecortin-Like Kinases
  • Gene Knockdown Techniques
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Neurons / metabolism
  • Parkinson Disease / metabolism*
  • Protein Serine-Threonine Kinases / metabolism*
  • alpha-Synuclein / metabolism*


  • Intracellular Signaling Peptides and Proteins
  • alpha-Synuclein
  • DCLK1 protein, human
  • Doublecortin-Like Kinases
  • Dclk1 protein, mouse
  • Protein Serine-Threonine Kinases