Chatting with the neighbors: crosstalk between Rho-kinase (ROCK) and other signaling pathways for treatment of neurological disorders

Abstract

ROCK inhibition has been largely applied as a strategy to treat neurodegenerative diseases (NDDs) and promising results have been obtained in the recent years. However, the underlying molecular and cellular mechanisms are not fully understood and different models have been proposed for neurodegenerative disorders. Here, we aim to review the current knowledge obtained for NDDs identifying common mechanisms as well as disease-specific models. In addition to the role of ROCK in different cell types such as neurons and microglia, we focus on the molecular signaling-pathways which mediate the beneficial effects of ROCK. Besides canonical ROCK signaling, modulation of neighboring pathways by non-canonical ROCK-crosstalk is a recurrent pattern in many NDD-model systems and has been suggested to mediate beneficial effects of ROCK-inhibition.

Keywords: alzheimer disease (AD); amyotrophic lateral sclerosis (ALS); huntington’s disease (HD); microglia; multiple sclerosis (MS); neuroinflammation; parkinson’s disease (PD); spinal muscular atrophy (SMA).

Figure 1

The ROCK-pathway in neurons and microglia. The regulatory network downstream of ROCK is defined by activating (arrows) or inactivating (blunted arrows) interactions. Induction of ROCK-activity leads to an up- or down-regulation of downstream targets, respectively (effects of upregulated ROCK-activity represented by red arrows). ROCK controls actomyosin contractility (canonical signaling, green) as well as Akt- and ERK-activity (non-canonical crosstalk, blue). ROCK-dependent profilin phosphorylation reduces its recycling capacity for globular (G)-actin leading to decreased turnover between filamentous (F) and G-actin. Cofilin-phosphorylation inactivates its F-actin severing activity resulting in less F-actin nucleation. Phosphorylation and inactivation of myosin light chain phosphatase (MLCP) induces myosin activity facilitating retrograde flow of F-actin. Together, those changes lead to a collapsing growth cone and inhibit axonal regeneration processes (reviewed in Lowery and Van Vactor, ; Gomez and Letourneau, 2014). ROCK phosphorylates and activates PTEN which in turn inactivates Akt. Similarly, ERK-activity is negatively regulated by ROCK. Neurotrophic Akt- and ERK-pathways are well described agonists of neuronal survival. However, also neuronal morphology is targeted by Akt/ERK signaling thereby influencing neuronal regeneration processes. The role of ROCK activity in microglia-activation is less understood. However, cytoskeletal alterations in ROCK-inhibitor treated cells implicate an involvement of canonical signaling, while ROCK-crosstalk has not been evaluated in microglia yet.

Figure 2

Beneficial effects of ROCK-inhibition in neurodegeneration – an integrated model. Neurodegenerative and neuroinflammatory processes (gray arrows) in different NDDs and in multiple sclerosis (MS) can be reversed by ROCK-inhibition (green arrows). Neuronal degeneration in Spinal Muscular Atrophy (SMA), Amyotrophic Lateral Sclerosis (ALS), Alzheimer's Disease (AD), Parkinson's Disease (PD), and Huntington's Disease (HD) lead to a microglia-intrinsic ROCK-induction necessary for microglia-activation. Activated microglia form engulfing “gliapses” with degenerating neurons subsequently phagocytosing neuronal debris. Moreover, they secret factors, which activate ROCK in neurons, thereby inhibiting axonal regeneration. Activated microglia can enter a “vicious circle” of chronic neuroinflammation attacking healthy neurons leading to neuronal degeneration and death. In MS, chronic neuroinflammation might be induced by microglia-activation and Blood-Brain Barrier (BBB) breakdown. ROCK-inhibition interferes with different pathomechanistic alterations in NDDs (green arrows). Down-regulation of ROCK-hyper-activity in microglia leads to their inactivation, while neuron-intrinsic ROCK-inhibition triggers axonal regeneration via canonical ROCK-signaling controlling actomyosin contractility. Additionally, ROCK-inhibition activates neurotrophic pathway-signaling via non-canonical crosstalk leading to a neuronal rescue. Besides those general effects, ROCK-inhibition specifically interferes with disease-specific molecular pathomechanisms. In AD and HD, neuronal aggregate toxicity is attenuated by ROCK-inhibition, while cytoskeletal dysregulations involving profilin represent the underlying mechanism in SMA.