Objective: Objective: To investigate Neurotinib, a newly developed allosteric c-Abl inhibitor, as a neuroprotective agent in a murine GBA1-associated Parkinson’s disease (PD) model.

Background: The c-Abl is a non-receptor tyrosine kinase with multiple biological functions across cell types. In neurons, overactivation of c-Abl promotes changes in several neuronal pathways, including apoptosis. Activation of c-Abl in neurons from patients with familial and sporadParkinson’sson disease (PD) triggers parkin and a-synuclein (SNCA) phosphorylation, accumulating toxic parkin substrates and a-syn aggregation. Thus, c-Abl activation impacts multiple mechanisms contributing to the pathogenesis of PD, and its inhibition is a promising therapeutic strategy.

Method: Variants in the glucocerebrosidase (GCase) gene, GBA1 are a risk factor for PD. We generated a murine model of GBA1-associated PD, Gba1^+/-;SNCA^A53T, to analyze the effect of partial GCase deficiency on the neurological progression of mouse phenotypes in vivo. We treated 42 PD and 14 WT controls between 10-12 months old mice with Neurotinib-infused chow and compared them to 31 PD mice receiving chow without the drug. Behavioral testing and PD symptoms monitoring was performed until the humane endpoint was reached, euthanasia performed, and tissues collected.

Results: Administration of Neurotinib in chow (67ppm) yielded substantial levels in WTmouse brains (between 0.65 and 1.10 mmol/kg).  Behavioral evaluations of the treated versus untreated Gba1^+/-;SNCA^A53T mice showed a statistically significant (p-value <0.0001 to 0.05) effect of Neurontinib. Survival analyses indicated that treated mice live significantly longer with milder symptoms (p-value= 0.0014). Finally, midbrain protein evaluations showed that the treatment significantly decreased neuronal levels of phosphorylated c-Abl and a-synuclein (p-value < 0.0001 to 0.05). Microglial and astrocyte activation was decreased, and GCase activity increased in the treated mice.

Conclusion: Our data demonstrate the efficacy and stability of Neurotinib in the brain and suggests that c-Abl inhibition is neuroprotective in a PD mouse model. RNAseq and proteomic analyses will be performed on brain to identify pathways affected by c-Abl inhibition. Ultimately, we plan to develop Neurotinib as a new therapeutic agent for PD with and without GBA1 variants.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/neurotinib-a-brain-penetrant-c-abl-inhibitor-prevents-activation-and-phosphorylation-of-c-abl-kinase-and-alpha-synuclein/