| Autor: |
Vázquez-Vélez, Gabriel E., Gonzales, Kristyn A., Revelli, Jean-Pierre, Adamski, Carolyn J., Naini, Fatemeh Alavi, Bajić, Aleksandar, Craigen, Evelyn, Richman, Ronald, Heman-Ackah, Sabrina M., Wood, Matthew J. A., Rousseaux, Maxime W. C., Zoghbi, Huda Y. |
| Předmět: |
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| Zdroj: |
Journal of Neuroscience; 1/8/2020, Vol. 40 Issue 2, p459-477, 19p |
| Abstrakt: |
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] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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