Evaluating the Role of Lin-11, Isl-1, and Mec-3 Kinases in Dopaminergic Neurodegeneration in a Subacute 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Model of Parkinson's Disease.

Abstract

The malfunctioning of microtubules is highly correlated with neurodegenerative disorders such as Parkinson's disease (PD), although whether it is a cause or an effect of neurodegeneration is yet unknown. Lin-11, Isl-1, and Mec-3 kinases (LIMKs), being one of the important kinases, regulate the neuronal cytoskeleton by controlling the phosphorylation of the cofilin/actin-depolymerizing factor. Recently, we showed that upregulation of phosphorylated LIMK1 (p-LIMK1) affects the microtubule dynamics in a central nervous system traumatic injury. The goal of this study is to correlate the expression of LIMK1 with dopaminergic neuron death in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of PD, one of the well-established subacute models of PD, where the neurotoxin acts via inhibition of mitochondrial complex I of the electron transport chain. Herein, we found that LIMK1 expression was increased and correlated to dopaminergic neuronal death. Finally, we demonstrated that the treatment with LIMK inhibitor BMS-5 significantly reversed the neurodegeneration, along with an upregulation of the dynamic tubulins, indicating the relevance of LIMKs and microtubule dynamics in neurodegeneration. Therefore, targeting the microtubules, an integral part of the neuronal cytoskeleton and neurite formation, can be a promising strategy to combat degeneration of dopaminergic neurons.