rho kinase and synuclein

Parkinson's disease (PD) is marked by the gradual degeneration of dopaminergic neurons and the intracellular build-up of Lewy bodies rich in α-synuclein protein. This impairs various aspects of the mitochondria including the generation of ROS, biogenesis, dynamics, mitophagy etc. Mitochondrial dynamics are regulated through the inter and intracellular movement which impairs mitochondrial trafficking within and between cells. This inter and intracellular mitochondrial movement plays a significant role in maintaining neuronal dynamics in terms of energy and growth...

Most patients with ovarian cancer (OC) are diagnosed at a late stage when there are very few therapeutic options and a poor prognosis. This is due to the lack of clearly defined underlying mechanisms or an oncogenic addiction that can be targeted pharmacologically, unlike other types of cancer. Here, we identified protein tyrosine kinase 7 (PTK7) as a potential new therapeutic target in OC following a multiomics approach using genetic and pharmacological interventions. We performed proteomics analyses upon PTK7 knockdown in OC cells and identified novel downstream effectors such as synuclein-γ (SNCG), SALL2, and PP1γ, and these findings were corroborated in ex vivo primary samples using PTK7 monoclonal antibody cofetuzumab...

Parkinson's disease (PD) is a complex and widespread neurodegenerative disease characterized by depletion of midbrain dopaminergic (DA) neurons. Key issues are the development of therapies that can stop or reverse the disease progression, identification of dependable biomarkers, and better understanding of the pathophysiological mechanisms of PD. RhoA-ROCK signals appear to have an important role in PD symptoms, making it a possible approach for PD treatment strategies. Activation of RhoA-ROCK (Rho-associated coiled-coil containing protein kinase) appears to stimulate various PD risk factors including aggregation of alpha-synuclein (αSyn), dysregulation of autophagy, and activation of apoptosis...

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder, but the disease-modifying therapies focusing on the core pathological changes are still unavailable. Rho-associated protein kinase (ROCK) has been suggested as a promising target for developing neuroprotective therapies in PD. OBJECTIVE: We aimed to explore the promotion of α-synuclein (α-syn) clearance in a rat model. METHODS: In a rat model induced by unilateral injection of adeno-associated virus of serotype 9 (AAV9) expressing A53T α-syn (AAV9-A53T-α-syn) into the right substantia nigra, we aimed to investigate whether Fasudil could promote α-syn clearance and thereby attenuate motor impairments and dopaminergic deficits...

Protein aggregation is a hallmark of diverse neurodegenerative diseases. Multiple lines of evidence have revealed that protein aggregates can penetrate inside cells and spread like prions. How such aggregates enter cells remains elusive. Through a focused siRNA screen targeting genes involved in membrane trafficking, we discovered that mutant SOD1 aggregates, like viruses, exploit cofilin-1 to remodel cortical actin and enter cells. Upstream of cofilin-1, signalling from the RHO GTPase and the ROCK1 and LIMK1 kinases controls cofilin-1 activity to remodel actin and modulate aggregate entry...

Neuroprotection refers to the relative preservation of neuronal structure and function. Neuroprotective agents refer to substances that are capable of preserving brain function and structure. Currently, there are no neuroprotective agents available that can effectively relieve the progression of Parkinson's disease. In this work, five novel 4-aminopyridine derivatives, including three amides and two ureas, were designed, synthesized, and evaluated using the rat PC12 mice pheochromocytoma cell line as an in vitro model...

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, yet disease-modifying treatments do not currently exist. Rho-associated protein kinase (ROCK) was recently described as a novel neuroprotective target in PD. Since alpha-synuclein (α-Syn) aggregation is a major hallmark in the pathogenesis of PD, we aimed to evaluate the anti-aggregative potential of pharmacological ROCK inhibition using the isoquinoline derivative Fasudil, a small molecule inhibitor already approved for clinical use in humans...

Accumulation of α-synuclein (α-syn) is pivotally implicated in the pathogenesis of Parkinson׳s disease (PD), and enhancing its clearance might be a promising strategy in PD treatment. It has recently been shown that Rho kinase (ROCK) activation is involved in many neurodegenerative diseases, and some ROCK inhibitors might promote the degradation of abnormal protein aggregates. However, it is not known if fasudil, the only ROCK inhibitor available in clinical setting, could promote the degradation of α-syn, and ameliorate the α-syn induced neurotoxicity...

Microglia activation and inflammatory factors in brain microenvironment are associated with degeneration of neurons in the substantia nigra (SN) of Parkinson's disease (PD) patients and various PD models. There is increasing evidence that the Rho/ROCK (Rho kinase) signalling pathway may play a critical role in the inflammatory response, and ROCK inhibitor has been reported to have neuroprotective effects. In this study, we examined the neuroprotective potential and possible mechanism of ROCK inhibitor Fasudil in an intranasal lipopolysaccharide (LPS)-induced PD model...

Accumulation of α-synuclein (Asyn) in neuronal perikarya and dystrophic neurites is characteristic of idiopathic and familial Parkinson's disease. In this study, we investigated the relationship between α-synuclein expression and neurite outgrowth-maturation using MN9D dopaminergic cells and demonstrated key features of Asyn regulation in hippocampal neurons. Neurite elongation elicited by inhibition of Rho GTPase activity with C3 transferase or by db-cAMP treatment was associated with marked reduction of α-synuclein mRNA and protein expression...

Studies of Parkinson's disease (PD) have been hindered by lack of access to affected human dopaminergic (DA) neurons. Here, we report generation of induced pluripotent stem cells that carry the p.G2019S mutation (G2019S-iPSCs) in the Leucine-Rich Repeat Kinase-2 (LRRK2) gene, the most common PD-related mutation, and their differentiation into DA neurons. The high penetrance of the LRRK2 mutation and its clinical resemblance to sporadic PD suggest that these cells could provide a valuable platform for disease analysis and drug development...

Antidepressant drugs can exert significant effects on the mood of a patient suffering major depression and other disorders. These drugs generally have pharmacological actions on the uptake or metabolism of the neurotransmitters serotonin, noradrenaline and, to a lesser extent, dopamine. However, there are many aspects of antidepressant action we do not understand. We have applied proteomic analysis in a rat hippocampal model in an attempt to identify relevant molecules that operate in pathways functionally relevant to antidepressant action...

Synuclein-gamma is aberrantly expressed in more than 70% of stage III/IV breast and ovarian carcinomas. Ectopic overexpression of synuclein-gamma enhanced MDA-MB-435 cell migration in vitro and metastasis in a nude mouse model. However, the mechanism of how synuclein-gamma promotes cell motility is not clear. In our previous studies, we showed that synuclein-gamma overexpression activates ERK. In the present study, we overexpressed synuclein-gamma in several breast and ovarian cancer cell lines and evaluated the effect of synuclein-gamma on the activity of small G-protein RHO family members...

Two widely expressed mammalian phosphatidylcholine (PC)-specific phospholipases D (PLD), PLD1 and PLD2, have been identified. Recombinantly expressed PLD2 has high basal activity and is insensitive to GTP-binding protein activators of PLD1 [Colley, W. C., et al. (1997) Curr. Biol. 7, 191-201]. To investigate the regulation of PLD2 we isolated PLD2, from mouse brain by immunoaffinity chromatography. The native and recombinant proteins have indistinguishable properties: PLD2 is potently activated by phosphoinositides with a vicinal 4,5-phosphate pair but is not stimulated by guanosine 5'-O-(3-thio triphosphate)-activated ADP-ribosylation factor-1, Rho family GTP-binding proteins, or protein kinases C-alpha, or -beta1...