LATS Inhibitor Protects 6-OHDA Induced Neuronal Cell Death In Vitro and In Vivo

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder marked by progressive motor dysfunction. Dopaminergic neurons in the substantia nigra are likely the main cause of PD onset. The Hippo signaling pathway regulates organ size and tumor suppression. The Yes-associated protein (YAP) is a nuclear effector of the Hippo signaling pathway, and activation of YAP may be beneficial in several neurodegenerative diseases. In this study, we examined the effects of compound A [N-(tert-butyl)-2-(pyridin-4-yl)-1,7-naphthyridin-4-amine], a large tumor suppressor kinase (LATS) inhibitor, on 6-hydroxydopamine (6-OHDA)-induced cell damage in vitro and in vivo. In human neuroblastoma SH-SY5Y cells, compound A showed a protective effect against 6-OHDA-induced cell death without exhibiting any cytotoxicity. In order to investigate the effects of compound A on dopaminergic neurons, compound A was orally administrated to mice twice a day for 21 d. Next, mouse brains were harvested to assess the expression of (1) a dopaminergic neuron marker and (2) a YAP transcriptional target. Treatment of mice with 6-OHDA suppressed the expression of tyrosine hydroxylase (TH), a dopaminergic neuron marker, and compound A (3 mg/kg, per os) administration ameliorated the TH expression levels. In addition, compound A upregulated the mRNA expression levels of connective tissue growth factor (CTGF), a YAP transcriptional target. These results suggest that activation of the Hippo signaling pathway by LATS inhibition may be used as a novel therapeutic target for treating PD.