Targeting the Arginylation Pathway for Neuroprotection After SCI
Abstract
The effects of spinal cord injury (SCI), including lifelong disability, depression, neuropathic pain, and autonomic dysfunction, affect more than 42,000 wounded Warriors and 1.25 million civilians in the United States. SCI also negatively impacts the lives of the families of the injured, caregivers, and the military healthcare system. Inhibiting neuronal cell apoptosis during the secondary phase of tissue damage is critical to reducing the degree of lost neurological function. To achieve neuroprotection, medications are highly desirable because most SCI events take place in complex environments or circumstances such as in combat or a car accident or a fall in a remote area, which makes access to advanced interventions, such as invasive and surgical procedures, nearly impossible. However, currently there is a lack of effective neuroprotective drugs for the acute treatment of SCI. In this study, we will directly address this need by validating protein arginylation as a drug target for SCI treatment, and by determining the efficacy, safety, and optimal conditions of suramin, a potent arginylation inhibitor that has been used for other diseases in human, for treating SCI in the acute phase. Earlier studies found that, following experimental nerve crush, there is an acute upsurge in neural arginylation, a form of post-translational modification in which an extra arginine is added to proteins by the catalysis of arginyltransferase 1 (ATE1). Arginylation is known to prime proteins for degradation through the ubiquitin pathway by the “N-end rule” principle. We have recently demonstrated that arginylation is a critical regulator of cell stress and apoptosis in response to a broad range of injurious conditions including heat, oxidative and osmotic stresses, which are involved in SCI. We found that knockout of ATE1 and antagonism of arginylation can engender cells to evade cell death by disrupting the cellular stress response. In our preliminary study, we have found that, although ATE1 exhibits a low basal expression and low arginylation activity in the normal central nervous system (CNS) of rodents, its expression and activity are robustly increased acutely after SCI and are largely localized to spinal motor neurons and their axonal projections. Consistently, when we reduce ATE1 in neuronal cells by RNA knockdown or suppress arginylaction activity by a chemical inhibitor suramin, these treatments protect neuronal cells from oxidative stressors. Furthermore, the application of suramin in a rat SCI model showed promising protective effects on neuronal morphology and locomotor function. These results have led us to propose that the suppression of ATE1-mediated arginylation can provide neuroprotective effects in SCI. The overall goal of this proposal is to define the therapeutic window and optimal application conditions for the arginylation inhibitor suramin, as a neuroprotective approach following SCI and build upon our initial proof-of-concept efficacy in SCI studies. We will further validate ATE1 as a feasible drug target after SCI using transgenic knockout animals. Considering the known CNS bioavailability, low toxicity, and long serum half-life of suramin, we will also test the possibility of achieving prophylactic protection with suramin after SCI. Overall, our proposed studies will generate a strong rationale for the treatment for SCI with arginylation inhibitors and move the technology readiness of this approach further towards clinical translation in human SCI treatment with a drug currently used in man.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110588
Entities
People
- Damien D Pearse
Organizations
- United States Army
- University of Miami