New insights on the regulators and inhibitors of RhoA-ROCK signalling in Parkinson's disease.

Abstract

A multifaceted and widely prevalent neurodegenerative disease, Parkinson's disease (PD) is typified by the loss of dopaminergic neurons in the midbrain. The discovery of novel treatment(s) that can reverse or halt the course of the disease progression along with identifying the most reliable biomarker(s) in PD remains the crucial concern. RhoA in its active state has been demonstrated to interact with three distinct domains located in the central coiled-coil region of ROCK. RhoA appears to activate effectors most frequently by breaking the intramolecular autoinhibitory connections, which releases functional domains from the effector protein. Additionally, RhoA is highly expressed in the nervous system and it acts as a central molecule for its several downstream effector proteins in multiple signalling pathways both in neurons and glial cells. Mitochondrial dysfunction, vesicle transport malfunction and aggregation of α-Synuclein, a presynaptic neuronal protein genetically and neuropathologically associated with PD. While the RhoA-ROCK signalling pathway appears to have a significant role in PD symptoms, suggesting it could be a promising target for therapeutic interventions. Thus, this review article addresses the potential involvement of the RhoA-ROCK signalling system in the pathophysiology of neurodegenerative illnesses, with an emphasis on its biology and function. We also provide an overview of the state of research on RhoA regulation and its downstream biological activities, focusing on the role of RhoA signalling in neurodegenerative illnesses and the potential benefits of RhoA inhibition as a treatment for neurodegeneration.