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Doublecortin-like Kinase 1 Regulates α-Synuclein Levels and Toxicity.
- Source :
-
Journal of Neuroscience . 1/8/2020, Vol. 40 Issue 2, p459-477. 19p. - Publication Year :
- 2020
-
Abstract
- 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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *SERINE/THREONINE kinases
*PARKINSON'S disease
*GENETIC code
*GENETIC disorders
Subjects
Details
- Language :
- English
- ISSN :
- 02706474
- Volume :
- 40
- Issue :
- 2
- Database :
- Academic Search Index
- Journal :
- Journal of Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 141262436
- Full Text :
- https://doi.org/10.1523/JNEUROSCI.1076-19.2019