Objective: Evaluate the impact of a novel Rho-associated kinase (ROCK) inhibitor on alpha-synuclein (a-syn) pathology, neuroinflammation, and dopamine neurodegeneration in the AAV-a-syn overexpression and a-syn preformed fibril (PFF) rodent models of synucleinopathy.
Background: Actin cytoskeleton dynamics, neuroinflammation, and neuronal survival are regulated by ROCK signaling, making it a promising target for neurodegenerative diseases like Parkinson’s Disease (PD). In PD, a-syn pathology contributes to dopamine neurodegeneration and neuroinflammatory responses. Previous studies have shown that ROCK inhibition may be neuroprotective by modulating microglial reactivity, enhancing axonal regeneration, and reducing pathological a-syn accumulation. In this study, we investigate the effects of a novel ROCK inhibitor with improved potency and blood-brain barrier penetrance, on a-syn accumulation, neuroinflammation, and neurodegeneration using the AAV-a-syn and a-syn PFF rodent models of synucleinopathy.
Method: Experiment 1: Rats received unilateral, intranigral injections of AAV2/5 overexpressing human a-syn. Experiment 2: Rats received unilateral intrastriatal injections of mouse a-syn PFFs. Following surgery, rats received daily ROCK inhibitor or vehicle by oral administration. Rats were euthanized 1, 2, or 4 months post-surgery. Post-mortem outcome measures included immunohistochemical assessments of dopamine neurons and inflammatory markers in the substantia nigra (SN), dopamine and metabolites in the striatum, and RNA sequencing in the SN.
Results: ROCK inhibition resulted in significant protection of nigral dopamine neurons from AAV-a-syn overexpression and a significant reduction in microgliosis. In contrast, ROCK inhibition did not provide neuroprotection from a-syn PFF-induced nigrostriatal degeneration. RNA sequencing results are pending.
Conclusion: Our results demonstrate that our novel ROCK inhibitor was neuroprotective against a-syn overexpression induced toxicity, but not a-syn inclusion induced toxicity. These findings suggest differences between the toxic mechanisms of the AAV a-syn and the a-syn PFF models of PD. Determination of the neuroprotective potential of ROCK inhibition, as well as other therapeutic approaches, requires a comprehensive understanding of the pathogenic mechanisms of both a-syn models and validation of these mechanisms in PD tissue.
To cite this abstract in AMA style:
M. Kubik, J. Mackeigan, A. Stoll, J. Patterson, J. Lipton, K. Steece-Collier, A. Cole-Strauss, C. Kemp, J. Howe, K. Miller, F. Manfredsson, S. Celano, K. Luk, C. Sortwell. Disease Modifying Potential of a Novel ROCK Inhibitor in Rodent Models of Synucleinopathy [abstract]. Mov Disord. 2025; 40 (suppl 1). https://www.mdsabstracts.org/abstract/disease-modifying-potential-of-a-novel-rock-inhibitor-in-rodent-models-of-synucleinopathy/. Accessed October 5, 2025.« Back to 2025 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/disease-modifying-potential-of-a-novel-rock-inhibitor-in-rodent-models-of-synucleinopathy/