Objective: To explore c-Abl kinase activation and neuron death pathway in Parkinson’s Disease (PD) mouse model. Assess neuroprotection natural compounds, Rosmarinic acid (RA) with proven antioxidant effects by targeting the c-Abl-PARIS-PGC1α-Nrf1 pathway and p53-dependent neuron death.

Background: Oxidative stress induced due to PD has been linked to activating c-Abl kinase, a non-receptor tyrosine kinase found in the cytoplasm, nucleus, and mitochondria in the dopaminergic neurons. Activation of c-Abl kinase aberrantly phosphorylates Parkin, causing loss of its function. PARKIN loss of function disrupts its E3 Ubiquitinating potential and leads to accumulation of Parkin substrates (PARIS). PARIS accumulation in PD has been found to cause dopaminergic neuron death by targeting the PGC1α- Nrf-2 pathway as well as p53-mediated cell death

Method: MPP+ Iodide-induced PD mouse model was used to investigate the hypothesis proposed. C57BL/6 mice were randomly divided into five groups, namely, normal control, disease control, and RA (5 mg/kg, 10 mg/kg, 15 mg/kg), respectively. MPP⁺ Iodide was injected intraperitoneally to induce PD. Neurobehavioral tests to examine grip strength, bradykinesia, locomotor, and exploratory behaviour were performed using Actimeter analysis, Rota Rod apparatus, and pole test. Various biochemical tests performed (western blot for protein expression and rt-PCR for gene expression) and immunohistochemistry were performed.

Results: RA acid can be considered neuroprotective in MPP⁺ Induced PD motor symptoms by improving behavioural parameters as assessed in grip strength, rotarod, actimeter and pole test. RA also shown to be neuroprotective by acting through c-Abl-Parkin-PARIS- PGC1α pathway and thus restoring mitochondrial turnover in dopaminergic neurons in C57BL/6 mice. Furthermore, an investigation of the cell death pathway due to MPP+ insult was found to be regulated by p53, and its expression decreased after treatment with RA.

Conclusion: The results obtained in the current study, RA could be beneficial as neuroprotective in PD. Furthermore, strong evidence to support the behavioural, biochemical and molecular study correlation, is quintessential to make a conclusion of neuroprotective potential of RA in PD.

References: Zhang, Y. et al. Nonreceptor Tyrosine Kinase c-Abl-Mediated PHB2 Phosphorylation Aggravates Mitophagy Disorder in Parkinson’s Disease Model. Oxid. Med. Cell. Longev. 2022, 1–20 (2022).
Imam, S. Z. et al. Neuroprotective Efficacy of a New Brain-Penetrating C-Abl Inhibitor in a Murine Parkinson’s Disease Model. PLoS One 8, (2013).
Zhao, Y. et al. Rosmarinic acid protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurotoxicity in zebrafish embryos. Toxicol. Vitr. 65, 1–10 (2020).

« Back to 2025 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/exploring-neuroprotective-role-of-natural-compound-by-targeting-c-abl-kinase-in-parkinsons-disease/