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.

APC/C Cdh1 -Rock2 pathway controls dendritic integrity and memory

“…The overactivation of Rock signaling antagonizes dendrite stability, whereas Rock inhibition promotes microtubule assembly and restores dendritic arbor complexity (6)(7)(8). Consistent with these results, Rock has been considered a promising drug target for central nervous system disorders (4). However, the molecular mechanism that regulates Rock abundance and activity in neurological disorders is unknown.…”

“…APC/C Cdh1 Triggers the Ubiquitin-Dependent Degradation of the DendriteDestabilizing Protein Rock2. The activation of Rho signaling through Rock plays the role of a central mediator of dendrite destabilization (1,4,22). We noticed that both Rock isoforms, Rock1 and Rock2, contain a conserved KEN box motif, which targets proteins for ubiquitination by the ubiquitin ligase APC/C Cdh1 (9).…”

“…Dendritic disruption and loss of dendritic spines and synapses have been reported in schizophrenia and depression, as well as in neurodegenerative conditions, including Alzheimer's disease (AD), and after an excitotoxic insult during stroke (2,3). The serinethreonine Rho protein kinase (Rock), an effector of the RhoA GTPase (4), is a central regulator of the microtubule cytoskeleton in neurons. Rock is known to modify the number, morphology, and stability of dendrites in a variety of neuronal cell types, including cortical neurons (1,5).…”

Modulation of Microglial Activity by Rho-Kinase (ROCK) Inhibition as Therapeutic Strategy in Parkinson’s Disease and Amyotrophic Lateral Sclerosis

“…Therapeutic studies targeting ROCK have been performed in different models of NDD using different strategies to attenuate ROCK activity (reviewed in Hensel et al, 2015). Inhibition of ROCK can be achieved pharmacologically using small molecules targeting either both ROCK isoforms (e.g., Fasudil and Y-27632) or specifically ROCK2 (e.g., SR3677 and SLx-2119; Defert and Boland, 2017).…”

Topical Ripasudil Suppresses Retinal Ganglion Cell Death in a Mouse Model of Normal Tension Glaucoma

“…[14][15][16][17] There are two isoforms of ROCK: ROCK-1 and ROCK-2, and they are extensively distributed in various tissues 18 ; for example, in ocular tissues, they are expressed in the ciliary muscles, trabecular meshwork, iris, and retina. 19 The Rho/ ROCK pathway is involved in various neuropathological conditions, such as spinal cord injury, 20 Alzheimer's disease, 21 and demyelinating disease, 22,23 and ophthalmologic diseases, such as glaucoma, 24 corneal endothelial dysfunction, 25 diabetic retinopathy, 26 and age-related macular degeneration. 27 ROCK signaling has therefore attracted interest as a potential therapeutic target for these diseases.…”