Abstract
Neurodegenerative diseases are characterized by the progressive degeneration of neurons in the central and peripheral nervous system (CNS, PNS), resulting in a reduced innervation of target structures and a loss of function. A shared characteristic of many neurodegenerative diseases is the infiltration of microglial cells into affected brain regions. During early disease stages microglial cells often display a rather neuroprotective phenotype, but switch to a more pro-inflammatory neurotoxic phenotype in later stages of the disease, contributing to the neurodegeneration. Activation of the Rho kinase (ROCK) pathway appears to be instrumental for the modulation of the microglial phenotype: increased ROCK activity in microglia mediates mechanisms of the inflammatory response and is associated with improved motility, increased production of reactive oxygen species (ROS) and release of inflammatory cytokines. Recently, several studies suggested inhibition of ROCK signaling as a promising treatment option for neurodegenerative diseases. In this review article, we discuss the contribution of microglial activity and phenotype switch to the pathophysiology of Parkinson’s disease (PD) and Amyotrophic lateral sclerosis (ALS), two devastating neurodegenerative diseases without disease-modifying treatment options. Furthermore, we describe how ROCK inhibition can influence the microglial phenotype in disease models and explore ROCK inhibition as a future treatment option for PD and ALS.
Highlights
The idea that neurodegenerative disorders (NDD) are primarily caused by a particular susceptibility of neuronal subpopulations to damaging insults is challenged by the observation that a pronounced infiltration of microglia into affected brain regions is a common hallmark of NDD
We show how ROCK inhibition can influence the microglial phenotype, discuss the microglial contribution to the pathophysiology of Parkinson’s disease (PD) and Amyotrophic lateral sclerosis (ALS) and explore ROCK inhibition as a treatment option for PD and ALS
Even though there are no studies showing that ROCK activity is increased in a certain microglial phenotype, there are reports from different models showing that inhibition of ROCK leads to a phenotypic shift from ‘‘M1’’ towards ‘‘M2’’ microglia, suggesting that ROCK activation is necessary for maintenance of the pro-inflammatory ‘‘M1’’ phenotype
Summary
The idea that neurodegenerative disorders (NDD) are primarily caused by a particular susceptibility of neuronal subpopulations to damaging insults is challenged by the observation that a pronounced infiltration of microglia into affected brain regions is a common hallmark of NDD. One major regulator of microglial activity is the Rho-kinase (ROCK) signaling pathway. Active ROCK phosphorylates numerous downstream targets which are involved in regulation of cell shape and motility as well as apoptosis and cell survival. In microglial cells the ROCK pathway is involved in regulation of migration, phagocytosis and release of inflammatory cytokines and mediates the microglial phenotype (Yan et al, 2012; Borrajo et al, 2014a). Inhibition of the ROCK pathway could be a promising treatment option for NDD. We show how ROCK inhibition can influence the microglial phenotype, discuss the microglial contribution to the pathophysiology of PD and ALS and explore ROCK inhibition as a treatment option for PD and ALS
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